Stem Cell Treatment Alzheimer's Disease - ASCI - Asian Stem Cell Institute

Stem Cell Treatment Alzheimer's Disease - ASCI - Asian Stem ...
http://www.stem-cell-regeneration.com/alzheimers-disease?tmp...
Stem Cell Treatments for Alzheimer's Disease are now available at ASCI Alzheimer's disease (AD) is the most common form of dementia; it worsens as it progresses, and eventually leads to death. It was rst described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, AD is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050. Although Alzheimer's disease develops differently for every individual, there are many common symptoms. Early symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common symptom is difculty in remembering recent events. When AD is suspected, the diagnosis is usually conrmed with tests that evaluate behaviour and thinking abilities, often followed by a brain scan if available.
Causation
The cause for most Alzheimer's cases is still essentially unknown (except for 1% to 5% of cases where genetic differences have been identied). Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deciency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinammation. A 2004 study found that deposition of amyloid plaques does not correlate well with
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neuron loss. This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurobrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result rst in malfunctions in biochemical communication between neurons and later in the death of the cells. Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau. Oxidative stress may be signicant in the formation of the pathology.
Alzheimers Stem Cell Treatment and stem cell therapy. Alzheimers treatment studies and stem cell protocols:
Valproic acid as a promising agent to combat Alzheimer's disease. Related Articles Valproic acid as a promising agent to combat Alzheimer's disease. Brain Res Bull. 2010 Jan 15;81(1):3-6 Authors: Zhang XZ, Li XJ, Zhang HY Abstract Alzheimer's disease (AD) is one of the most threatening diseases to the elderly population at present. However, there is no yet efficient therapeutic method to AD. Recently, accumulating evidence indicates that valproic acid (VPA), a widely used mood stabilizer and antiepileptic drug, has neuroprotective potential relevant to AD. Moreover, VPA can induce neurogenesis of neural progenitor/stem cells both in vitro and in vivo via multiple signaling pathways. Therefore, it is suggested that VPA is a promising agent to combat AD. PMID: 19748552 [PubMed - indexed for MEDLINE] Read more... Neuroscience: Alzheimer's disease. Related Articles Neuroscience: Alzheimer's disease. Nature. 2009 Oct 15;461(7266):895-7 Authors: Mucke L PMID: 19829367 [PubMed - indexed for MEDLINE] Read more... Neurogenesis and Alzheimer's disease: Biology and pathophysiology in mice and men. Related Articles Neurogenesis and Alzheimer's disease: Biology and pathophysiology in mice and men. Curr Alzheimer Res. 2010 Mar;7(2):113-25 Authors: Marlatt MW, Lucassen PJ Abstract The hippocampus is critical for learning and memory and heavily affected in dementia. The presence of stem cells in this structure has led to an increased interest in the phenomenon of adult neurogenesis and its role in hippocampal functioning. Not surprising, investigators of Alzheimer's disease have also evaluated adult neurogenesis due to its responsiveness to hippocampal damage. Although causal relationships have not been established, many factors known to impact neurogenesis in the hippocampus, are implicated in the pathogenesis of AD. Also, adult neurogenesis has been proposed to reflect a "neurogenic reserve" that may determine vulnerability to hippocampal dysfunction and neurodegeneration. Since neurogenesis is modifiable, stimulation of this process, or the potential use of stem cells, recruited endogenously or implanted by transplantation, has been speculated as a possible treatment of neurodegenerative disorders. As the structural and molecular mechanisms governing adult neurogenesis are important for evaluating therapeutic strategies, we will here review collective literature findings and speculate about the future of this field with a focus on findings from Alzheimer's mouse models. Continued research in this area and use of these models is critical for evaluating if neurogenesis based therapeutic strategies will indeed have the potential to aid those with degenerative conditions. PMID: 19860727 [PubMed - indexed for MEDLINE]
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Read more... Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Related Articles Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells. 2010 Feb;28(2):329-43 Authors: Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS Abstract Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta peptide (Abeta) and the formation of neurofibrillary tangles. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been suggested as a potential therapeutic approach to prevent various neurodegenerative disorders, including AD. However, the actual therapeutic impact of BM-MSCs and their mechanism of action in AD have not yet been ascertained. The aim of this study was therefore to evaluate the therapeutic effect of BM-MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin one (PS1) double-transgenic mice. Here we show that intracerebral transplantation of BM-MSCs into APP/PS1 mice significantly reduced amyloid beta-peptide (Abeta) deposition. Interestingly, these effects were associated with restoration of defective microglial function, as evidenced by increased Abeta-degrading factors, decreased inflammatory responses, and elevation of alternatively activated microglial markers. Furthermore, APP/PS1 mice treated with BM-MSCs had decreased tau hyperphosphorylation and improved cognitive function. In conclusion, BM-MSCs can modulate immune/inflammatory responses in AD mice, ameliorate their pathophysiology, and improve the cognitive decline associated with Abeta deposits. These results demonstrate that BM-MSCs are a potential new therapeutic agent for AD. PMID: 20014009 [PubMed - indexed for MEDLINE] Read more... Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal diseases? Related Articles Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal diseases? Cent Nerv Syst Agents Med Chem. 2009 Dec;9(4):307-30 Authors: Schmitz G, Leuthuser-Jaschinski K, Ors E Abstract Microglial cells, in contrast to other central nervous system cell types such as neurons and macroglia, are of myeloid origin. They constitute the immune cells of the brain and are involved in neuroinflammatory and neurodegenerative processes. Moreover, diseases of the central nervous system with an inflammatory component are characterized by the migration of bone marrow-derived monocytes into the brain where they differentiate into microglia, the "tissue macrophages" of the nervous system, bearing a therapeutic potential for certain diseases by transplantation of bone marrow-derived hematopoietic stem and progenitor cells. Due to their common origin, microglial cells and monocytes/macrophages share expression of many surface receptors and signalling proteins. Moreover, there is overlap in the expression of many genes related to Alzheimer s disease. Activation of resident and blood-derived microglia in diseases of the central nervous system can be both beneficial, e.g. by degradation of protein aggregates, and detrimental, e.g. by secretion of neurotoxic factors. This review summarizes the current knowledge about the role of microglia in neurodegenerative diseases with a focus on Alzheimer s disease. Moreover, we present data how neuroinflammation is reflected by cellular changes in peripheral blood enabling the use of blood monocytes/macrophages for diagnosis, therapeutic target finding and outcome monitoring of neurodegenerative disorders. In summary, blood monocytes as microglia orthologues are an important model system to study the role of microglia in the pathogenesis of neurodegenerative diseases. They are suitable biomarker targets for diagnosis and prognosis and maybe also therapy of central nervous system disease. PMID: 20021364 [PubMed - indexed for MEDLINE] Read more... Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. Related Articles Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. J Neuroinflammation. 2009;6:39 Authors: Ryu JK, Cho T, Wang YT, McLarnon JG Abstract BACKGROUND: Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in Alzheimer's disease (AD) brain are largely unknown and a primary objective of this work was to demonstrate possible efficacy of NPC administration in an animal model of AD. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons or by conferring neuroprotection with enhancement of neurotrophic factors or diminishing levels of neurotoxic agents. Since chronic inflammation is a characteristic property of AD brain, we considered that transplantation of NPC could have particular utility in inhibiting ongoing inflammatory reactivity. We
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have tested intrahippocampal transplantation of NPC for efficacy in attenuating inflammatory responses and for neuroprotection in beta-amyloid (Abeta1-42) peptide-injected rat hippocampus. METHODS: Spheres of neural progenitor cells were grown from dissociated telencephalon tissue of rat embryos. NPC were infected with lentiviral vector green fluorescent protein (GFP) with subsequent cell transplantation into rat hippocampus previously injected (3 d prior) with Abeta1-42 peptide or PBS control. Immunohistochemical analysis was carried out (7 d post-NPC transplantation, 10 d post-peptide/PBS injection) for GFP, microgliosis (Iba-1 marker), astrogliosis (GFAP marker), neuron viability (MAP-2 marker) and levels of the proinflammatory cytokine, TNF-alpha. RESULTS: Successful infection of cultured NPC with lentiviral vector green fluorescent protein (GFP) was demonstrated prior to cell transplantation into rat hippocampus. In vivo, immunohistochemical staining showed migration of GFP-positive cells, in a region of dentate gyrus between Abeta1-42/PBS injection site and NPC transplantation site, was increased x2.8-fold with Abeta1-42 compared to PBS injection. Double immunostaining in peptide-injected brain indicated GFP association with nestin and GFAP, but not MAP-2. Cell-specific immunostaining showed marked increases in microgliosis and astrogliosis in Abeta1-42-injected brain (respective increases of x4.3- and x4.6-fold compared with PBS injection). NPC transplantation significantly reduced microgliosis (by 38%) but not astrogliosis in peptide-injected hippocampus. The proinflammatory cytokine TNF-alpha was elevated by 6.7-fold (peptide vs PBS injection) with NPC administration attenuating levels of TNF-alpha (by 40%). Peptide-injected brain demonstrated neuronal loss (MAP-2 staining reduced by 45% vs PBS injection) with NPC transplantation effective in conferring neuroprotection (26% recovery of neurons). CONCLUSIONS: These findings indicate efficacy for NPC transplantation in an animal model of AD with effects consistent with cellular actions to attenuate inflammatory reactivity induced by intrahippocampal peptide injection. PMID: 20030829 [PubMed - indexed for MEDLINE] Read more... Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in amyloid(1-40) injured rat hippocampus. Related Articles Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in amyloid-(1-40) injured rat hippocampus. J Alzheimers Dis. 2010;21(4):1233-47 Authors: Li Z, Gao C, Huang H, Sun W, Yi H, Fan X, Xu H Abstract Alzheimer's disease (AD) is characterized by the dysfunction or loss of a vulnerable group of neurons. At present, only a few options exist for treating neurodegenerative diseases effectively. Advances in stem cell research have raised the hope and possibility for therapy in neurodegenerative diseases. In AD transgenic animal models, stem cell transplantation has been demonstrated to reverse behavioral deficits. Our recent study demonstrates that neural precursor cells, derived from embryonic stem (ES) cells, improve memory dysfunction in rats caused by injections of amyloid- peptide (1-40) (A) in the dorsal hippocampus. However, the underlying mechanisms remain unknown. The present study tests a murine ES cell-based transplantation approach in rats subjected to A injection into the hippocampus dentate gyrus. Efficacy of cell therapy with regard to graft survival, neuronal yield and diversity, synapse formation of the grafted cells, and the behavioral improvements was determined after transplanting ES cell-derived neural precursors into the hippocampus of adult rats. Here, we show that grafted cells can survive, and differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. More importantly, transplanted cells demonstrate characteristics of proper synapse formation between host and grafted neural cells. Thus, our observations show that an ES cell-based transplantation approach may be promising in the treatment of AD. PMID: 21504128 [PubMed - indexed for MEDLINE] Read more... Stem cells in human neurodegenerative disorders--time for clinical translation? Related Articles Stem cells in human neurodegenerative disorders--time for clinical translation? J Clin Invest. 2010 Jan;120(1):29-40 Authors: Lindvall O, Kokaia Z Abstract Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment. PMID: 20051634 [PubMed - indexed for MEDLINE] Read more...
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Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease? Related Articles Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease? J Alzheimers Dis. 2010;20(2):395-408 Authors: Lopez-Toledano MA, Ali Faghihi M, Patel NS, Wahlestedt C Abstract Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short-term memory loss. The deposition of amyloid-beta (Abeta) 1-42 into senile plaques is an established feature of AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere consequence of the events leading to AD. Nevertheless, Abeta toxicity has been probed in vitro and in vivo and increased production or decreased clearance of Abeta peptides are reported to play a major role in the development of AD. Treatment of neural stem cells with Abeta in vitro induces neuronal differentiation. Increased neurogenesis has been also described in AD patients as well as in amyloid-beta protein precursor (AbetaPP) transgenic mice. Adult neurogenesis is greatly enhanced in young AbetaPP transgenic mice, before other AD-liked pathologies, and reduced in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Abetainduced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker. PMID: 20164555 [PubMed - indexed for MEDLINE] Read more... Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. Related Articles Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010 Apr;9(2):168-73 Authors: Hickman SE, El Khoury J Abstract Alzheimer's disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of beta-amyloid (Abeta) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Abeta levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Abeta deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease. PMID: 20205643 [PubMed - indexed for MEDLINE] Read more... Impact of the CD40-CD40L dyad in Alzheimer's disease. Related Articles Impact of the CD40-CD40L dyad in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010 Apr;9(2):149-55 Authors: Giunta B, Rezai-Zadeh K, Tan J Abstract As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future. PMID: 20205645 [PubMed - indexed for MEDLINE] Read more... Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Related Articles Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503 Authors: Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung
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EJ, Thompson RF, Brinton RD Abstract Our previous analyses showed that allopregnanolone (APalpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APalpha significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APalpha reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APalpha-induced survival of neural progenitors was significantly correlated with APalpha-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Abeta, may contribute to the cognitive phenotype of AD, and that APalpha could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease. PMID: 20231471 [PubMed indexed for MEDLINE] Read more... Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. Related Articles Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. Recent Pat CNS Drug Discov. 2010 Jun;5(2):109-17 Authors: Holscher C Abstract Analogues of the incretins Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) have been developed to treat type 2 diabetes mellitus. They are protease resistant and have a longer biological half life than the native peptides. Some of these novel analogues can cross the blood-brain barrier, have neuroprotective effects, activate neuronal stem cells in the brain, and can improve cognition. The receptors for GIP and GLP-1 are expressed in neurons, and both GIP and GLP-1 are expressed and released as transmitters by neurons. GIP analogues such as DAla(2)GIP and GLP-1 analogues such as liraglutide enhance synaptic plasticity in the brain and also reverse the betaamyloid induced impairment of synaptic plasticity. In mouse models of Alzheimer's disease, GLP-1 analogues Val(8)GLP-1 and liraglutide prevent memory impairment and the block of synaptic plasticity in the brain. Since two GLP- 1 analogues exendin-4 (Exenatide, Byetta) and liraglutide (Victoza) are already on the market as treatments for Type 2 diabetes, and others are in late stage clinical trials, these drugs show promise as treatments for neurodegenerative diseases such as Alzheimer's disease. Currently, there are three patents covering native GLP-1 and different GLP-1 analogues and one patent for the use of GIP and different GIP analogues for the treatment of neurodegenerative diseases. PMID: 20337586 [PubMed - indexed for MEDLINE] Read more... [Positron emission tomography imaging of cell transplantation in a rat model of Alzheimer's disease]. Related Articles [Positron emission tomography imaging of cell transplantation in a rat model of Alzheimer's disease]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2010 Apr;32(2):210-4 Authors: He TT, Zhang JM, Shen L, Yao SL, Tian JH Abstract OBJECTIVE: To explore the value of positron emission tomography (PET) in the Alzheimer's disease (AD) rat model verification and in monitoring the therapeutic effectiveness of cell transplantation. METHODS: A beta(1-40) hippocampus injected rat model was successfully established and neural stem cells were injected into hippocampus. Results of behavior tests and histological examinations were compared between model group and graft group, and then the N-methyl-[(11)C]2-(4 methylaminophenyl)-6-hydroxybenzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) imaging were performed to observe whether the result of imaging was matched with behavior test and histological examination. RESULTS: The Morris water maze showed that the latent period of the escape was significantly longer in model group than in control group (P Read more... Gene- and cell-based approaches for neurodegenerative disease. Related Articles Gene- and cell-based approaches for neurodegenerative disease. Adv Exp Med Biol. 2010;671:117-30 Authors: Urbaniak Hunter K, Yarbrough C, Ciacci J Abstract Neurodegenerative diseases comprise an important group ofchronic diseases that increase in incidence with rising age. In particular, the two most common neurodegenerative diseases are Alzheimer's disease and Parkinson's disease, both of which will be discussed below. A third, Huntington's
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disease, occurs infrequently, but has been studied intensely. Each of these diseases shares characteristics which are also generalizeable to other neurodegenerative diseases: accumulation ofproteinaceous substances that leads inexorably to selective neuronal death and decline in neural function. Treatments for these diseases have historically focused on symptomatic relief, but recent advances in molecular research have identified more specific targets. Additionally, stem cell therapy, immunotherapy and trophic-factor delivery provide avenues for neuronal protection that may alter the natural progression of these devastating illnesses. Upcoming clinical trials will evaluate treatment strategies and provide hope that translational research will decrease the onset of debilitating disability associated with neurodegenerative disease. PMID: 20455500 [PubMed - indexed for MEDLINE] Read more... Bone marrow-derived mesenchymal stem cells attenuate amyloid -induced memory impairment and apoptosis by inhibiting neuronal cell death. Related Articles Bone marrow-derived mesenchymal stem cells attenuate amyloid -induced memory impairment and apoptosis by inhibiting neuronal cell death. Curr Alzheimer Res. 2010 Sep;7(6):540-8 Authors: Lee JK, Jin HK, Bae JS Abstract Amyloid (A) peptide plays a central role in neuronal apoptosis, promoting oxidative stress, lipid peroxidation, caspase pathway activation and neuronal loss. Our previous study has shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) reduce A deposition when transplanted into acutely-induced Alzheimer's disease (AD) mice brain. However, the impact of reduced A deposition on memory impairment and apoptosis by BM-MSCs has not yet been investigated. Therefore, the aim of the present study was to investigate the neuroprotective mechanism of BM-MSCs in vitro and in vivo. We found that BM-MSCs attenuated A-induced apoptotic cell death in primary cultured hippocampal neurons by activation of the cell survival signaling pathway. These anti-apoptotic effects of BM-MSCs were also observed in an acutely-induced AD mice model produced by injecting A intrahippocampally. In addition, BM-MSCs diminished A -induced oxidative stress and spatial memory impairment in the in vivo model. These findings lead us to hypothesize that BM-MSCs ameliorate A -induced neurotoxicity and cognitive decline by inhibiting apoptotic cell death and oxidative stress in the hippocampus. These findings provide support for a potentially beneficial role for BM-MSCs in the treatment of AD. PMID: 20455866 [PubMed - indexed for MEDLINE] Read more... Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation. Related Articles Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation. Neurobiol Aging. 2012 Mar;33(3):588-602 Authors: Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, Yang YS, Suh JG, Lee BH, Jin HK, Bae JS Abstract Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid- peptide (A) deposition, -secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with A deposition in AD mice. PMID: 20471717 [PubMed - indexed for MEDLINE] Read more... Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow. Related Articles Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow. Am J Pathol. 2010 Jul;177(1):346-54 Authors: Keene CD, Chang RC, Lopez-Yglesias AH, Shalloway BR, Sokal I, Li X, Reed PJ, Keene LM, Montine KS, Breyer RM, Rockhill JK, Montine TJ Abstract A complex therapeutic challenge for Alzheimer's disease (AD) is minimizing deleterious aspects of microglial activation while maximizing beneficial actions, including phagocytosis/clearance of amyloid beta (Abeta) peptides. One potential target is selective suppression of microglial prostaglandin E(2) receptor subtype 2 (EP2) function, which influences microglial phagocytosis and elaboration of
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neurotoxic cytokines. To test this hypothesis, we transplanted bone marrow cells derived from wild-type mice or mice homozygous deficient for EP2 (EP2(-/-)) into lethally irradiated 5-month-old wild-type or APPswe-PS1DeltaE9 double transgenic AD mouse model recipients. We found that cerebral engraftment by bone marrow transplant (BMT)-derived wild-type or EP2(-/-) microglia was more efficient in APPswe-PS1DeltaE9 than in wild-type mice, and APPswePS1DeltaE9 mice that received EP2(-/-) BMT had increased cortical microglia compared with APPswe-PS1DeltaE9 mice that received wild-type BMT. We found that myeloablative irradiation followed by bone marrow transplant-derived microglia engraftment, rather than cranial irradiation or BMT alone, was responsible for the approximate one-third reduction in both Abeta plaques and potentially more neurotoxic soluble Abeta species. An additional 25% reduction in cerebral cortical Abeta burden was achieved in mice that received EP2(-/-) BMT compared with mice that received wild-type BMT. Our results provide a foundation for an adult stem cell-based therapy to suppress soluble Abeta peptide and plaque accumulation in the cerebrum of patients with AD. PMID: 20522650 [PubMed - indexed for MEDLINE] Read more... Why scientific details are important when novel technologies encounter law, politics, and ethics. Related Articles Why scientific details are important when novel technologies encounter law, politics, and ethics. J Law Med Ethics. 2010;38(2):204-11 Authors: Goldstein L Abstract This paper focuses on the issue of what to do if a couple who generates embryos chooses to lawfully, and in their (and my) view, ethnically discard those embryos. Specifically, is it appropriate to use the cells that come from "excess" embryos in medical research instead of discarding them when a couple has ceased trying to have any additional children? PMID: 20579243 [PubMed - indexed for MEDLINE] Read more... The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Related Articles The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett. 2010 Aug 30;481(1):30-5 Authors: Lee HJ, Lee JK, Lee H, Shin JW, Carter JE, Sakamoto T, Jin HK, Bae JS Abstract The neuropathological hallmarks of Alzheimer's disease (AD) include the presence of extracellular amyloid-beta peptide (Abeta) in the form of amyloid plaques in the brain parenchyma and neuronal loss. The mechanism associated with neuronal death by amyloid plaques is unclear but oxidative stress and glial activation has been implicated. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are being scrutinized as a potential therapeutic tool to prevent various neurodegenerative diseases including AD. However, the therapeutic impact of hUCB-MSCs in AD has not yet been reported. Here we undertook in vitro work to examine the potential impact of hUCB-MSCs treatment on neuronal loss using a paradigm of cultured hippocampal neurons treated with Abeta. We confirmed that hUCB-MSCs co-culture reduced the hippocampal apoptosis induced by Abeta treatment. Moreover, in an acute AD mouse model to directly test the efficacy of hUCB-MSCs treatment on AD-related cognitive and neuropathological outcomes, we demonstrated that markers of glial activation, oxidative stress and apoptosis levels were decreased in AD mouse brain. Interestingly, hUCB-MSCs treated AD mice demonstrated cognitive rescue with restoration of learning/memory function. These data suggest that hUCB-MSCs warrant further investigation as a potential therapeutic agent in AD. PMID: 20600610 [PubMed - indexed for MEDLINE] Read more... The novel protein MANI modulates neurogenesis and neurite-cone growth. Related Articles The novel protein MANI modulates neurogenesis and neurite-cone growth. J Cell Mol Med. 2011 Aug;15(8):1713-25 Authors: Mishra M, Akatsu H, Heese K Abstract Neuronal regeneration and axonal re-growth in the injured mammalian central nervous system remains an unsolved field. To date, three myelin-associated proteins [Nogo or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are known to inhibit axonal regeneration via activation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor [NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo-1]. In the present study we describe the novel protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiation into catecholaminergic neurons. Yeast two-hybrid screening and co-immunoprecipitation experiments confirmed the cell division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. We show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite outgrowth. Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases. PMID: 20716133 [PubMed - indexed for MEDLINE]
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Read more... Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice. Related Articles Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice. Korean J Physiol Pharmacol. 2010 Aug;14(4):229-33 Authors: Yang HJ, Joo Y, Hong BH, Ha SJ, Woo RS, Lee SH, Suh YH, Kim HS Abstract Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease. PMID: 20827337 [PubMed] Read more... Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice. Related Articles Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice. Cell Transplant. 2011;20(3):371-9 Authors: Kern DS, Maclean KN, Jiang H, Synder EY, Sladek JR, Bjugstad KB Abstract Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of Alzheimer's disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid- or APP. These clusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were similar to those described by others who also found extracellular proteinous granules in the brains of non-DS mice engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD. PMID: 20875225 [PubMed - indexed for MEDLINE] Read more... [The feasibility of synthetic enhancer substances for preventive nanotherapy]. Related Articles [The feasibility of synthetic enhancer substances for preventive nanotherapy]. Neuropsychopharmacol Hung. 2010 Sep;12(3):395-403 Authors: Miklya I Abstract Nanotechnology, the great promise of the 21st century, may revolutionize also the art of healing. Previously unexpected broadening of diagnostic procedures and methods to deliver specific drugs acting in lower than nanomolecular concentrations right to the target cells may play a crucial role in the rapid development of preventive medicine. In this context, (-)-deprenyl/selegiline, a drug developed 40 years ago and still world-wide used to treat Parkinson's disease, Alzheimer's disease and depression, by enhancing the activity of catecholaminergic neurons in the brain stem via a previously unknown mechanism [catecholaminergic activity enhancer (CAE) effect], is a highly promising experimental tool for further research in this direction. The same fits for (-)-BPAP, the newly developed enhancer substance, 100 times more potent than (-)-deprenyl, which in contrast to the latter is not only an enhancer of the catecholaminergic neurons but also of the serotonergic neurons in the brain stem. Tiny amounts of enhancer substances are closed in liposomes and marked with a specific signal to help identify the exact location of the target cells, through the activation of which the drug exerts its specific enhancer effect. The method also offers an approach to better understand the up-to-the-present unknown mechanism of the enhancer effect. PMID: 20962359 [PubMed - indexed for MEDLINE] Read more...
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Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. Related Articles Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem. 2010 Dec 31;285(53):41337-47 Authors: Popkie AP, Zeidner LC, Albrecht AM, D'Ippolito A, Eckardt S, Newsom DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ Abstract Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3 and Gsk-3, are constitutively active, largely inhibitory kinases involved in signal transduction. Underscoring their biological significance, altered Gsk-3 activity has been implicated in diabetes, Alzheimer disease, schizophrenia, and bipolar disorder. Here, we demonstrate that deletion of both Gsk-3 and Gsk-3 in mouse embryonic stem cells results in reduced expression of the de novo DNA methyltransferase Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and Igf2r and hypomethylation of their corresponding imprinted control regions. Treatment of wild-type embryonic stem cells and neural stem cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA hypomethylation at these imprinted loci. We show that inhibition of Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of Akt also results in reduced DNA methylation at these imprinted loci. Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary, we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci. PMID: 21047779 [PubMed - indexed for MEDLINE] Read more... Leaf and stem of Vitis amurensis and its active components protect against amyloid protein (25-35)-induced neurotoxicity. Related Articles Leaf and stem of Vitis amurensis and its active components protect against amyloid protein (25-35)-induced neurotoxicity. Arch Pharm Res. 2010 Oct;33(10):1655-64 Authors: Jeong HY, Kim JY, Lee HK, Ha do T, Song KS, Bae K, Seong YH Abstract This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid protein (A) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 M A (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 g/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of which were induced by A (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol A (25-35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans--viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i) and the generation of ROS induced by A (25-35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against A (25-35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer's disease. PMID: 21052941 [PubMed - indexed for MEDLINE] Read more... The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. Related Articles The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J Biol Chem. 2011 Jan 28;286(4):2596-606 Authors: Delarasse C, Auger R, Gonnord P, Fontaine B, Kanellopoulos JM Abstract The amyloid precursor protein (APP) is cleaved by - and -secretases to generate the -amyloid (A) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) patient brains. Non-amyloidogenic processing of APP by -secretases leads to proteolytic cleavage within the A peptide sequence and shedding of the soluble APP ectodomain (sAPP), which has been reported to be endowed with neuroprotective properties. In this work, we have shown that activation of the purinergic receptor P2X7 (P2X7R) stimulates sAPP release from mouse neuroblastoma cells expressing human APP, from human neuroblastoma cells and from mouse primary astrocytes or neural progenitor cells. sAPP shedding is inhibited by P2X7R antagonists or knockdown of P2X7R with specific small interfering RNA (siRNA) and is not observed in neural cells from P2X7Rdeficient mice. P2X7R-dependent APP-cleavage is independent of extracellular calcium and strongly inhibited by hydroxamate-based metalloprotease inhibitors, TAPI-2 and GM6001. However, knockdown of a disintegrin and metalloproteinase-9 (ADAM9), ADAM10 and ADAM17 by specific siRNA, known to have -secretase activity, does not block the P2X7R-dependent non-amyloidogenic pathway. Using several specific pharmacological inhibitors, we demonstrate that the mitogen-activated protein kinase modules Erk1/2 and JNK are involved in P2X7R-dependent -secretase activity. Our study suggests that P2X7R, which is expressed in hippocampal neurons and glial cells, is a potential therapeutic target in AD. PMID: 21081501 [PubMed - indexed for MEDLINE]
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Read more... Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells induced by oligomeric amyloid -peptide. Related Articles Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells induced by oligomeric amyloid -peptide. J Neurochem. 2011 Feb;116(4):522-9 Authors: Shruster A, Eldar-Finkelman H, Melamed E, Offen D Abstract Neural stem cells give rise to new hippocampal neurons throughout adulthood. Defects in neurogenesis are associated with cognitive dysfunctions, such as Alzheimer disease (AD). Our understanding of the signals controlling this process is limited. The present in vitro study explored the manner in which the Wnt signaling pathway regulates the differentiation of hippocampal progenitors (HPs) into neurons under the influence of amyloid (42) (A(42) ). The results showed that oligomeric A(42) reduced neuronal differentiation. This process was accompanied by a reduction in active -catenin levels and proneural gene expression. The addition of Wnt3a increased the neuronal differentiation of A(42) -treated HPs, at the expense of astrocyte differentiation. The effect of Wnt signaling was attributable to progenitor cell differentiation to the neuronal lineage, and not to increased proliferation or rescue of neurons. The interruption of Wnt signaling by oligomeric A(42) may have clinical implications for the treatment of impaired neurogenesis in AD. PMID: 21138436 [PubMed - indexed for MEDLINE] Read more... Stem cells for the treatment of neurodegenerative diseases. Related Articles Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther. 2010;1(5):37 Authors: Dantuma E, Merchant S, Sugaya K Abstract Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising. PMID: 21144012 [PubMed - in process] Read more... [Treatment of Alzheimer's disease and future approaches]. Related Articles [Treatment of Alzheimer's disease and future approaches]. Therapie. 2010 Sep-Oct;65(5):429-37 Authors: Forette F, Hauw JJ Abstract The progressive neuronal loss in Alzheimer's disease leads to neurochemical abnormalities which provide the basis for symptomatic treatments. Four cholinesterase inhibitors were released in this indication. Meta-analyses have confirmed a beneficial effect on cognitive functioning and activities of daily living. The NMDA receptor antagonist, memantine, was also approved for the treatment of moderate to severe and may be associated. Progress in the patho-physiology of the disease offers some hope of new treatments acting on the cerebral lesions. The amyloid hypothesis allowed the emergence of active or passive immunotherapies, and of secretase inhibitors or modulators. Recent studies have targeted the P tau protein. The brain plasticity and the uses of stem cells offer more distant hope. PMID: 21144478 [PubMed - indexed for MEDLINE] Read more... Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic Approaches. 27-28 September 2010, Jersey City, NJ, USA. Related Articles Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic Approaches. 27-28 September 2010, Jersey City, NJ, USA. IDrugs. 2010 Dec;13(12):825-7 Authors: Wolfe MS Abstract The 11th Alzheimer's Disease Drug Discovery International Conference, held in Jersey City, NJ, USA, included topics covering new therapeutic developments in the field of Alzheimer's disease. This conference report highlights selected presentations on the use of patient-specific stem cells, and neuroprotection, regeneration and cognitive enhancement strategies for the prevention or treatment of Alzheimer's disease. Investigational approaches discussed include allopregnanolone for neuron protection and regeneration, PDE5 inhibitors as therapeutics, upregulating the protein Klotho to prevent cognitive decline, targeting memory deficits induced by A42 oligomers, inhibiting striatalenriched protein tyrosine phosphatase (STEP) for treating neuropsychiatric disorders, and agonism of GABA-A receptors to treat age-related cognitive deficits. PMID: 21154134 [PubMed - indexed for MEDLINE] Read more... -amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons. Related Articles -amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic
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neurons. PLoS One. 2010;5(12):e15600 Authors: Wicklund L, Leo RN, Strmberg AM, Mousavi M, Hovatta O, Nordberg A, Marutle A Abstract Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the -amyloid (A) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric A1-40 and A1-42 (nM-M concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric A1-40 increased the number of functional neurons, whereas oligomeric A1-42 suppressed the number of functional neurons. Interestingly, oligomeric A exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar A1-40 and A1-42 induced gliogenesis. These findings indicate that A1-42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of A. PMID: 21179413 [PubMed - indexed for MEDLINE] Read more... Neurogenesis, NSCs, pathogenesis and therapies for Alzheimer's disease. Related Articles Neurogenesis, NSCs, pathogenesis and therapies for Alzheimer's disease. Front Biosci (Schol Ed). 2011;3:178-90 Authors: Taupin P Abstract Neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals. Adult NSCs offer tremendous potential for cellular therapy for the treatment of neurological diseases and injuries, particularly of Alzheimer's disease (AD). The contribution of newly generated neuronal cells of the adult brain to the functioning of the nervous system remains to be elucidated. Neurogenesis is enhanced in the brain of patients with AD. Enhanced neurogenesis would contribute to regenerative attempts in AD, to compensate for the neuronal loss. Adult neurogenesis holds the potential to generate aneuploid cells, a landmark of AD pathology. Aneuploid newly generated neuronal cells in the adult brain would contribute to the pathogenesis of AD. Adult neurogenesis would not only be beneficial, but also detrimental for patients with AD. We will review and discuss the potential of adult NSCs for the treatment of AD and their contribution to the pathogenesis of the disease, as well as the development of novel drugs and therapies for treating AD. PMID: 21196368 [PubMed - indexed for MEDLINE] Read more... P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis. Related Articles P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis. J Cell Mol Med. 2011 Nov;15(11):2462-77 Authors: Mishra M, Heese K Abstract In the present study, we show that overexpression of the G-protein-coupled receptor (GPCR)-associated sorting protein p60TRP (transcription regulator protein) in neural stem cells (NSCs) and in a transgenic mouse model modulates the phosphorylation and proteolytic processing of amyloid precursor protein (App), N-cadherin (Cdh2), presenilin (Psen) and protein (Mapt). Our results suggest that p60TRP is an inhibitor of Bace1 (-site App cleaving enzyme) and Psen. We performed several apoptosis assays [Annexin-V, TdT-mediated dUTP Nick-End Labeling (TUNEL), caspase-3/7] using NSCs and PC12 cells (overexpressing p60TRP and knockdown of p60TRP) to substantiate the neuroprotective role of p60TRP. Functional analyses, both in vitro and in vivo, revealed that p60TRP promotes neurosynaptogenesis. Characterization of the cognitive function of p60TRP transgenic mice using the radial arm water maze test demonstrated that p60TRP improved memory and learning abilities. The improved cognitive functions could be attributed to increased synaptic connections and plasticity, which was confirmed by the modulation of the -aminobutyric acid receptor system and the elevated expression of microtubule-associated protein 2, synaptophysin and Slc17a7 (vesicle glutamate transporter, Vglut1), as well as by the inhibition of Cdh2 cleavage. In conclusion, interference with the p60TRP/ GPCR/secretase signalling pathway might be a new therapeutic target for the treatment of Alzheimer's disease (AD). PMID: 21199326 [PubMed - indexed for MEDLINE] Read more... Impact of induced pluripotent stem cells on the study of central nervous system disease. Related Articles Impact of induced pluripotent stem cells on the study of central nervous system disease. Curr Opin
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Genet Dev. 2011 Jun;21(3):354-61 Authors: Cundiff PE, Anderson SA Abstract The derivation of pluripotent stem cells from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed. PMID: 21277194 [PubMed - indexed for MEDLINE] Read more... Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice. Related Articles Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice. Exp Gerontol. 2011 Aug;46(8):628-36 Authors: Yang H, Wen SR, Zhang GW, Wang TG, Hu FX, Li XL, Wang DS Abstract Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS (2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's disease. PMID: 21277365 [PubMed - indexed for MEDLINE] Read more... Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's disease. Related Articles Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2011;24 Suppl 2:17-25 Authors: Prez-Gonzlez R, Antequera D, Vargas T, Spuch C, Bols M, Carro E Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid- (A) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and A pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and APP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in APP/PS1 mice. We estimated the number proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of A-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in APP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD. PMID: 21335656 [PubMed - indexed for MEDLINE] Read more... Stem cell factor and granulocyte colony-stimulating factor reduce -amyloid deposits in the brains of APP/PS1 transgenic mice. Related Articles Stem cell factor and granulocyte colony-stimulating factor reduce -amyloid deposits in the brains of APP/PS1 transgenic mice. Alzheimers Res Ther. 2011;3(2):8 Authors: Li B, Gonzalez-Toledo ME, Piao CS, Gu A, Kelley RE, Zhao LR Abstract INTRODUCTION: Alzheimer's disease (AD) is widely recognized as a serious public health problem and heavy financial burden. Currently, there is no treatment that can delay or stop the progressive brain damage in AD. Recently, we demonstrated that stem cell factor (SCF) in combination with granulocyte colonystimulating factor (G-CSF) (SCF+G-CSF) has therapeutic effects on chronic stroke. The purpose of the present study is to determine whether SCF+G-CSF can reduce the burden of -amyloid deposits in a mouse model of AD. METHODS: APP/PS1 transgenic mice were used as the model of AD. To track bone marrow-derived cells in the brain, the bone marrow of the APP/PS1 mice was replaced with the bone marrow from mice expressing green fluorescent protein (GFP). Six weeks after bone marrow transplantation, mice were randomly divided into a saline control group and a
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SCF+G-CSF-treated group. SCF in combination with G-CSF was administered subcutaneously for 12 days. Circulating bone marrow stem cells (CD117+ cells) were quantified 1 day after the final injection. Nine months after treatment, at the age of 18 months, mice were sacrificed. Brain sections were processed for immunohistochemistry to identify -amyloid deposits and GFP expressing bone marrow-derived microglia in the brain. RESULTS: Systemic administration of SCF+G-CSF to APP/PS1 transgenic mice leads to long-term reduction of -amyloid deposition in the brain. In addition, we have also observed that the SCF+G-CSF treatment increases circulating bone marrow stem cells and augments bone marrow-derived microglial cells in the brains of APP/PS1 mice. Moreover, SCF+G-CSF treatment results in enhancement of the co-localization of bone marrow-derived microglia and -amyloid deposits in the brain. CONCLUSIONS: These data suggest that bone marrow-derived microglia play a role in SCF+G-CSF-induced long-term effects to reduce -amyloid deposits. This study provides insights into the contribution of the hematopoeitic growth factors, SCF and G-CSF, to limit -amyloid accumulation in AD and may offer a new therapeutic approach for AD. PMID: 21406112 [PubMed] Read more... Genetic therapy for the nervous system. Related Articles Genetic therapy for the nervous system. Hum Mol Genet. 2011 Apr 15;20(R1):R28-41 Authors: Bowers WJ, Breakefield XO, Sena-Esteves M Abstract Genetic therapy is undergoing a renaissance with expansion of viral and synthetic vectors, use of oligonucleotides (RNA and DNA) and sequence-targeted regulatory molecules, as well as genetically modified cells, including induced pluripotent stem cells from the patients themselves. Several clinical trials for neurologic syndromes appear quite promising. This review covers genetic strategies to ameliorate neurologic syndromes of different etiologies, including lysosomal storage diseases, Alzheimer's disease and other amyloidopathies, Parkinson's disease, spinal muscular atrophy, amyotrophic lateral sclerosis and brain tumors. This field has been propelled by genetic technologies, including identifying disease genes and disruptive mutations, design of genomic interacting elements to regulate transcription and splicing of specific precursor mRNAs and use of novel non-coding regulatory RNAs. These versatile new tools for manipulation of genetic elements provide the ability to tailor the mode of genetic intervention to specific aspects of a disease state. PMID: 21429918 [PubMed - indexed for MEDLINE] Read more... Human embryonic stem cell therapies for neurodegenerative diseases. Related Articles Human embryonic stem cell therapies for neurodegenerative diseases. CNS Neurol Disord Drug Targets. 2011 Jun;10(4):440-8 Authors: Tomaskovic-Crook E, Crook JM Abstract There is a renewed enthusiasm for the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives. Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS cells. PMID: 21495960 [PubMed - indexed for MEDLINE] Read more... Stem cell therapy for Alzheimer's disease. Related Articles Stem cell therapy for Alzheimer's disease. CNS Neurol Disord Drug Targets. 2011 Jun;10(4):459-85 Authors: Abdel-Salam OM Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder which impairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the neurodegenerative process. Extracellular as well as intracellular deposition of beta-amyloid or Abeta (Abeta) protein, intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages.
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In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult neurogenesis may contribute to the pathogenesis of AD and other neurodegenerative disorders. An attempt at mobilizing this endogenous pool of resident stem-like cells provides another attractive approach for the treatment of AD. Studies in patients with AD indicated decreased hippocampal volume derived by neurodegeneration. Intriguingly, many drugs including antidepressants, lithium, acetyl cholinesterase inhibitors, and ginkgo biloba, were able to enhance the impaired neurogenesis in this disease process. This paved the way towards exploring the possible pharmacological manipulation of neurogenesis which would offer an alternative approach for the treatment of AD. PMID: 21495961 [PubMed - indexed for MEDLINE] Read more... Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic mouse model of Alzheimer's disease. Related Articles Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic mouse model of Alzheimer's disease. Neurosci Lett. 2011 Jun 15;497(1):6-10 Authors: Klinge PM, Harmening K, Miller MC, Heile A, Wallrapp C, Geigle P, Brinker T Abstract Encapsulated human mesenchymal stem cells(MSC) are studied in a double transgenic mouse model of Alzheimer's disease (AD) after intraventricular implantation at 3 months of age. Abeta 40/42 deposition, and glial (GFAP) and microglial (CD11b) immunoreactivity were investigated 2 months after transplantation of either native MSC or MSC transfected with glucagon-like peptide-1 (GLP-1). CD11b immunostaining in the frontal lobes was significantly decreased in the GLP-1 MSC group compared to the untreated controls. Also, the plaque associated GFAP immunoreactivity was only observed in one of four animals in the GLP-1 MSC group. Abeta 40 whole brain ELISA was decreased in the MSC group: 86.065.2 pg/ml (untreated control) vs. 78.6711.2 pg/ml (GLP-1 MSC group) vs.70.911.1 pg/ml (MSC group, p Read more... Stem cell factor plasma levels are decreased in Alzheimer's disease patients with fast cognitive decline after one-year follow-up period: the Pythia-study. Related Articles Stem cell factor plasma levels are decreased in Alzheimer's disease patients with fast cognitive decline after one-year follow-up period: the Pythia-study. J Alzheimers Dis. 2011;26(1):39-45 Authors: Laske C, Sopova K, Hoffmann N, Stransky E, Hagen K, Fallgatter AJ, Stellos K, Leyhe T Abstract Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination [MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score 4 after one year; n = 28) (fast versus slow cognitive decline: mean SD: 1051.1 178.7 versus 1237.9 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis. PMID: 21593573 [PubMed - indexed for MEDLINE] Read more... Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1 in an
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Alzheimer's disease mouse model. Related Articles Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1 in an Alzheimer's disease mouse model. Stem Cells. 2011 Jul;29(7):1075-89 Authors: Shin JW, Lee JK, Lee JE, Min WK, Schuchman EH, Jin HK, Bae JS Abstract Transplantation of bone marrow-derived stem cells (BMSCs) has been suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines. Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor (G-CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1 (SDF-1) on endogenous BM-derived hematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice received an intracerebral injection with SDF-1 to induce migration of mobilized BM-HPCs into brain. We found that the memory deficit in the AD mice was significantly improved by these treatments, but amyloid deposition was unchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1-green fluorescent protein (GFP) chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally, increased hippocampal neurogenesis and improved memory was observed in mice receiving combined G-CSF/AMD3100 and SDF-1, but not in controls or animals receiving each treatment alone. These results suggest that SDF-1 is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized by G-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants further investigation as a potential therapeutic option for the treatment of AD patients in the future. PMID: 21608078 [PubMed - indexed for MEDLINE] Read more... Amitriptyline-mediated cognitive enhancement in aged 3Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity. Related Articles Amitriptyline-mediated cognitive enhancement in aged 3Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity. PLoS One. 2011;6(6):e21660 Authors: Chadwick W, Mitchell N, Caroll J, Zhou Y, Park SS, Wang L, Becker KG, Zhang Y, Lehrmann E, Wood WH, Martin B, Maudsley S Abstract Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in cytotoxic dimer A load, compared to vehicle-treated 3TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD. PMID: 21738757 [PubMed - indexed for MEDLINE] Read more... Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer's disease. Related Articles Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer's disease. J Cell Mol Med. 2012 May;16(5):1060-73 Authors: Magga J, Savchenko E, Malm T, Rolova T, Pollari E, Valonen P, Lehtonen , Jantunen E, Aarnio J, Lehenkari P, Koistinaho M, Muona A, Koistinaho J Abstract Accumulation of amyloid (A) is a major hallmark in Alzheimer's disease (AD). Bone marrow derived monocytic cells (BMM) have been shown to reduce A burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficient phagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a method to obtain monocytic cells from BM-derived haematopoietic stem cells (HSC). Mouse or human HSC were isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were
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characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory stimulus. The phagocytic capacity was determined with A uptake assay in vitro and A degradation assay of natively formed A deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transduced with enhanced green fluorescent protein (eGFP) to determine the effect of gene modification on the potential of HSC-derived cells for therapeutic purposes. HSC-derived monocytic cells (HSCM) displayed inflammatory responses comparable to microglia and peripheral monocytes. We also show that HSCM contributed to A reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood HSC, indicating a potential therapeutic relevance for AD. PMID: 21777378 [PubMed indexed for MEDLINE] Read more... The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease. Related Articles The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease. Cell Adh Migr. 2011 Jul-Aug;5(4):280-92 Authors: Zhou ZD, Chan CH, Ma QH, Xu XH, Xiao ZC, Tan EK Abstract The amyloid-beta (A) peptide is the derivative of amyloid precursor protein (APP) generated through sequential proteolytic processing by - and -secretases. Excessive accumulation of A, the main constituent of amyloid plaques, has been implicated in the etiology of Alzheimer's disease (AD). It was found recently that the impairments of neurogenesis in brain were associated with the pathogenesis of AD. Furthermore recent findings implicated that APP could function to influence proliferation of neural progenitor cells (NPC) and might regulate transcriptional activity of various genes. Studies demonstrated that influence of neurogenesis by APP is conferred differently via its two separate domains, soluble secreted APPs (sAPPs, mainly sAPP) and APP intracellular domain (AICD). The sAPP was shown to be neuroprotective and important to neurogenesis, whereas AICD was found to negatively modulate neurogenesis. Furthermore, it was demonstrated recently that microRNA could function to regulate APP expression, APP processing, A accumulation and subsequently influence neurotoxicity and neurogenesis related to APP, which was implicated to AD pathogenesis, especially for sporadic AD. Based on data accumulated, secretase balances were proposed. These secretase balances could influence the downstream balance related to regulation of neurogenesis by AICD and sAPP as well as balance related to influence of neuron viability by A and sAPP. Disruption of these secretase balances could be culprits to AD onset. PMID: 21785276 [PubMed - indexed for MEDLINE] Read more... Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Related Articles Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans. 2011 Aug;39(4):891-7 Authors: Hlscher C Abstract Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by -amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin-like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization. PMID: 21787319 [PubMed indexed for MEDLINE] Read more...
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Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Related Articles Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiol Aging. 2012 Aug;33(8):1493-506 Authors: Singh C, Liu L, Wang JM, Irwin RW, Yao J, Chen S, Henry S, Thompson RF, Brinton RD Abstract We previously demonstrated that allopregnanolone (AP) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of AP to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. AP significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (A) whereas AP was ineffective subsequent to development of extraneuronal A plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in AP-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, AP significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that AP promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging. PMID: 21803451 [PubMed - indexed for MEDLINE] Read more... Neuronal differentiation of human mesenchymal stromal cells increases their resistance to A42 aggregate toxicity. Related Articles Neuronal differentiation of human mesenchymal stromal cells increases their resistance to A42 aggregate toxicity. J Alzheimers Dis. 2011;27(3):651-64 Authors: Cecchi C, Evangelisti E, Cascella R, Zampagni M, Benvenuti S, Luciani P, Deledda C, Cellai I, Wright D, Saccardi R, Peri A, Stefani M Abstract Cell therapy is a promising approach for the treatment of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. However, the presence of toxic aggregates in tissue raises the question of whether grafted stem cells are susceptible to amyloid toxicity before they differentiate into mature neurons. To address this question, we investigated the relative vulnerability of human mesenchymal stromal cells and their neuronally differentiated counterparts to A(42) oligomers and whether susceptibility correlates with membrane GM1 content, a key player in oligomer toxicity. We found that our cell model was highly susceptible to aggregate toxicity, whereas neuronal differentiation induced resistance to amyloid species. This data correlated well with the content of membrane GM1, levels of which decreased considerably in differentiated cells. These findings extend our knowledge of stem cell vulnerability to amyloid species, which remains a controversial issue, and confirm that amyloid-GM1 interactions play an important role in cell impairment. PMID: 21876252 [PubMed indexed for MEDLINE] Read more... Isolating nasal olfactory stem cells from rodents or humans. Related Articles Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011;(54) Authors: Girard SD, Devze A, Nivet E, Gepner B, Roman FS, Fron F Abstract The olfactory mucosa, located in the nasal cavity, is in charge of detecting odours. It is also the only nervous tissue that is exposed to the external environment and easily accessible in every living individual. As a result, this tissue is unique for anyone aiming to identify molecular anomalies in the pathological brain or isolate adult stem cells for cell therapy. Molecular abnormalities in brain diseases are often studied using nervous tissue samples collected post-mortem. However, this material has numerous limitations. In contrast, the olfactory mucosa is readily accessible and can be biopsied safely without any loss of sense of smell(1). Accordingly, the olfactory mucosa provides an "open window" in the adult human through which one can study developmental (e.g. autism, schizophrenia)(2-4) or neurodegenerative (e.g. Parkinson, Alzheimer) diseases(4,5). Olfactory mucosa can be used for either comparative molecular studies(4,6) or in vitro experiments on neurogenesis(3,7). The olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria(8-10). We recently developed a method to purify the adult stem cells located in the lamina
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propria and, after having demonstrated that they are closely related to bone marrow mesenchymal stem cells (BM-MSC), we named them olfactory ecto-mesenchymal stem cells (OE-MSC)(11). Interestingly, when compared to BM-MSCs, OE-MSCs display a high proliferation rate, an elevated clonogenicity and an inclination to differentiate into neural cells. We took advantage of these characteristics to perform studies dedicated to unveil new candidate genes in schizophrenia and Parkinson's disease(4). We and others have also shown that OE-MSCs are promising candidates for cell therapy, after a spinal cord trauma(12,13), a cochlear damage(14) or in an animal models of Parkinson's disease(15) or amnesia(16). In this study, we present methods to biopsy olfactory mucosa in rats and humans. After collection, the lamina propria is enzymatically separated from the epithelium and stem cells are purified using an enzymatic or a non-enzymatic method. Purified olfactory stem cells can then be either grown in large numbers and banked in liquid nitrogen or induced to form spheres or differentiated into neural cells. These stem cells can also be used for comparative omics (genomic, transcriptomic, epigenomic, proteomic) studies. PMID: 21876529 [PubMed indexed for MEDLINE] Read more... Stem cell technology for neurodegenerative diseases. Related Articles Stem cell technology for neurodegenerative diseases. Ann Neurol. 2011 Sep;70(3):353-61 Authors: Lunn JS, Sakowski SA, Hur J, Feldman EL Abstract Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases. PMID: 21905078 [PubMed - indexed for MEDLINE] Read more... AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Related Articles AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther. 2012 Jul;19(7):724-33 Authors: Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T Abstract Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid- peptide (A) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-A-targeted treatment of AD. PMID: 21918553 [PubMed - indexed for MEDLINE] Read more... Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-induced learning and memory deficit animals. Related Articles Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-induced learning and memory deficit animals. Cell Transplant. 2012;21(1):365-71 Authors: Park D, Joo SS, Kim TK, Lee SH, Kang H, Lee HJ, Lim I, Matsuo A, Tooyama I, Kim YB, Kim SU Abstract Alzheimer disease (AD) is a progressive neurodegenerative disease, which is characterized by loss of memory and cognitive function. In AD patients dysfunction of the cholinergic system is the main cause of cognitive disorders, and decreased activity of choline acetyltransferase (ChAT), an enzyme responsible for acetylcholine (ACh) synthesis, is observed. In the present
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study we investigated if brain transplantation of human neural stem cells (NSCs) genetically modified to encode ChAT gene improves cognitive function of kainic acid (KA)-induced learning deficit rats. Intrahippocampal injection of KA to hippocampal CA3 region caused severe neuronal loss, resulting in profound learning and memory deficit. F3.ChAT human NSCs transplanted intracerebroventricularly improved fully the learning and memory function of KA-induced learning deficit animals, in parallel with the elevation of ACh levels in cerebrospinal fluid. F3.ChAT human NSCs migrated to the KA-induced injury site (CA3) and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs expressing ChAT have lesion-tropic property and improve cognitive function of learning deficit model rats with hippocampal injury by increasing ACh level. PMID: 21929870 [PubMed - indexed for MEDLINE] Read more... Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles. Related Articles Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles. BMC Syst Biol. 2011;5:152 Authors: Zhang L, Ju X, Cheng Y, Guo X, Wen T Abstract BACKGROUND: Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD). While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC) differentiation by tmem59 is explored on the genome-level. RESULTS: We identified regulators of tmem59 during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred tmem59 related gene network including 36 genes, pou6f1 was identified to regulate tmem59 significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that tmem59 locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of pou6f1 could significantly up-regulate tmem59 expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including Ace, aqp1, arrdc3, cd14, cd59a, cds1, cldn1, cox8b, defb11, folr1, gdi2, mmp3, mgp, myrip, Ripk4, rnd3, and sncg. The localization of tmem59 related genes and functional-related gene groups based on the Gene Ontology (GO) annotation was also identified. CONCLUSIONS: Our findings suggest that the expression of tmem59 is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to identifying genes for AD. PMID: 21955788 [PubMed - indexed for MEDLINE] Read more... (1)H-MRS evaluation of therapeutic effect of neural stem cell transplantation on Alzheimer's disease in APP/PS1 double transgenic mice. Related Articles (1)H-MRS evaluation of therapeutic effect of neural stem cell transplantation on Alzheimer's disease in APP/PS1 double transgenic mice. J Alzheimers Dis. 2012;28(1):71-80 Authors: Chen SQ, Cai Q, Shen YY, Wang PJ, Teng GJ, Li MH, Zhang W, Zang FC Abstract The aim of this work was to explore the applicable value of (1)H-MRS evaluation on the treatment of Alzheimer's disease (AD) with neural stem cell (NSC) transplantation by quantitative analysis of metabolite changes in the hippocampal area in APP/PS1 transgenic (tg) mice. The tg mice (n = 30) aged 12 months were randomized into two subgroups: One receiving NSCs and the other receiving PBS transplantation in the bilateral hippocampal CA1 region. The wild-type mice (n = 15) were used as the control group. (1)H-MRS was performed before transplantation and 6 weeks after transplantation to measure the change of N-acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), choline (Cho), and creatine (Cr) in the hippocampus. Results showed NAA and Glu levels were increased and mI level was decreased in NSC group compared with the PBS group at six weeks after transplantation (p < 0.05). There was no significant difference in NAA and Glu (p > 0.05), and there was significant difference in mI (p < 0.05) between NSC and control groups. However, there was no significant difference in Cho before and after transplantation among the three groups (p > 0.05). Histology showed the number of neurons in the hippocampal CA1 region increased significantly in the NSC group than those in the PBS group (p < 0.05), and the number of astrocytes significantly decreased in the NSC group compared with the PBS group. Ultrastructure showed that the neurons in the NSC group were morphologically normal. In conclusion, (1)H-MRS can display intracranial metabolite changes before and after NSC transplantation in tg mice and has a applicable value in evaluating the therapeutic effect of NSCs on AD. PMID: 21955813 [PubMed - indexed for MEDLINE] Read more...
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Anti-A drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. Related Articles Anti-A drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. PLoS One. 2011;6(9):e25788 Authors: Yahata N, Asai M, Kitaoka S, Takahashi K, Asaka I, Hioki H, Kaneko T, Maruyama K, Saido TC, Nakahata T, Asada T, Yamanaka S, Iwata N, Inoue H Abstract BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid peptide (A), which is produced from amyloid precursor protein by - and -secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. METHODOLOGY/PRINCIPAL FINDINGS: We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, -secretase, and -secretase components, and were capable of secreting A into the conditioned media. A production was inhibited by -secretase inhibitor, -secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (A surge) and drastic decline of A production. CONCLUSIONS/SIGNIFICANCE: These results indicate that the hiPS cell-derived neuronal cells express functional and -secretases involved in A production; however, anti-A drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation. PMID: 21984949 [PubMed - indexed for MEDLINE] Read more... A-degrading enzymes: potential for treatment of Alzheimer disease. Related Articles A-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol. 2011 Nov;70(11):944-59 Authors: Miners JS, Barua N, Kehoe PG, Gill S, Love S Abstract There is increasing evidence that deficient clearance of -amyloid (A) contributes to its accumulation in late-onset Alzheimer disease (AD). Several A-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce A levels and protect against cognitive impairment in mouse models of AD. The activity of several A-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of A. The age- and disease-related changes in expression of more recently recognized A-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy. Regardless of the role of A-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge. The most promising current approaches include the peripheral administration of agents that enhance the activity of A-degrading enzymes and the direct intracerebral delivery of NEP by convection-enhanced delivery. In the longer term, genetic approaches to increasing the intracerebral expression of NEP or other A-degrading enzymes may offer advantages. PMID: 22002425 [PubMed - indexed for MEDLINE] Read more... Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid- plaques. Related Articles Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid- plaques. Cell Death Differ. 2012 Apr;19(4):680-91 Authors: Kim JY, Kim DH, Kim JH, Lee D, Jeon HB, Kwon SJ, Kim SM, Yoo YJ, Lee EH, Choi SJ, Seo SW, Lee JI, Na DL, Yang YS, Oh W, Chang JW Abstract Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-42 (A42) exposure induced a reduction of A42 in the medium as well as an overexpression of the A-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in timeand dose-dependent manners. In co-culturing with BV2 cells under A42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added A42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer's disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, A42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward A deposits. These data suggest that hUCB-MSC-
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derived sICAM-1 decreases A plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway. PMID: 22015609 [PubMed - indexed for MEDLINE] Read more... Intracerebroventricular transplantation of human amniotic epithelial cells ameliorates spatial memory deficit in the doubly transgenic mice coexpressing APPswe and PS1E9-deleted genes. Related Articles Intracerebroventricular transplantation of human amniotic epithelial cells ameliorates spatial memory deficit in the doubly transgenic mice coexpressing APPswe and PS1E9-deleted genes. Chin Med J (Engl). 2011 Sep;124(17):2642-8 Authors: Xue SR, Chen CF, Dong WL, Hui GZ, Liu TJ, Guo LH Abstract BACKGROUND: Human amniotic epithelial cells (HAECs), which have characteristics of both embryonic and pluripotent stem cells, are therefore a candidate in cell therapy without creating legal or ethical problems. In the present study, we aimed to investigate the effects of intracerebroventricular transplantation of HAECs on doubly transgenic mice of Alzheimer's disease (AD) coexpressing presenilin-1 (PS1) and mutant Sweden amyloid precursor protein (APPswe) genes. METHODS: The offspring mice genotypes were detected using PCR identification of APPswe and PS1 gene. The doubly transgenic (TG) mice (n = 20) and wild-type (WT) mice (n = 20) were randomly divided into two groups respectively: the transplantation group treated with HAECs and the control group with phosphate buffered saline. Six radial arm water maze test was used to assess the spatial memory in the TG and WT mice. Amyloid plaques and neurofibrillary tangles were analyzed using congo red and acid-silver methenamine staining respectively. Immunofluorescence cytochemistry was used to track the survival of HAECs. Immunohistochemistry was used to determine the expression of octamer-binding protein 4 (Oct-4) and Nanog in the HAECs. High performance liquid chromatography was used to measure acetylcholine in hippocampus. The density of cholinergic neurons in basal forebrain and nerve fibers in hippocampus was measured using acetylcholinesterase staining. RESULTS: Amyloid deposition occurred in hippocampus and frontal cortex in the double TG mice aged 8 months, but not in WT mice. The results also showed that transplanted HAECs can survive for at least 8 weeks and migrate to the third ventricle without immune rejection. The graft HAECs can also express the specific marker Oct-4 and Nanog of stem cell. Compared with the control group, transplantation of HAECs can not only significantly improve the spatial memory of the TG mice, but also increase acetylcholine concentration and the number of hippocampal cholinergic neurites. CONCLUSIONS: These results demonstrate that intracerebroventricular transplantation of HAECs can improve the spatial memory of the double TG mice. The higher content of acetylcholine in hippocampus released by more survived cholinergic neurites is one of the causes of this improvement. PMID: 22040417 [PubMed - indexed for MEDLINE] Read more... FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders. Related Articles FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders. Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48 Authors: Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T Abstract The adult hippocampus plays a central role in memory formation, synaptic plasticity, and neurogenesis. The subgranular zone of the dentate gyrus contains neural progenitor cells with self-renewal and multilineage potency. Transgene expression of familial Alzheimer's disease-linked mutants of -amyloid precursor protein (APP) and presenilin-1 leads to a significant inhibition of neurogenesis, which is potentially linked to age-dependent memory loss. To investigate the effect of neurogenesis on cognitive function in a relevant disease model, FGF2 gene is delivered bilaterally to the hippocampi of APP+presenilin-1 bigenic mice via an adenoassociated virus serotype 2/1 hybrid (AAV2/1-FGF2). Animals injected with AAV2/1-FGF2 at a pre- or postsymptomatic stage show significantly improved spatial learning in the radial arm water maze test. A neuropathological investigation demonstrates that AAV2/1-FGF2 injection enhances the number of doublecortin, BrdU/NeuN, and c-fos-positive cells in the dentate gyrus, and the clearance of fibrillar amyloid- peptide (A) in the hippocampus. AAV2/1-FGF2 injection also enhances long-term potentiation in another APP mouse model (J20) compared with control AAV2/1-GFP-injected littermates. An in vitro study confirmed the enhanced neurogenesis of mouse neural stem cells by direct AAV2/1-FGF2 infection in an A oligomer-sensitive manner. Further, FGF2 enhances A phagocytosis in primary cultured microglia, and reduces A production from primary cultured neurons after AAV2/1-FGF2 infection. Thus, our data indicate that virus-mediated FGF2 gene delivery has potential as an alternative therapy of Alzheimer's disease and possibly other neurocognitive disorders. PMID: 22042871 [PubMed - indexed for MEDLINE] Read more...
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Nicotine: specific role in angiogenesis, proliferation and apoptosis. Related Articles Nicotine: specific role in angiogenesis, proliferation and apoptosis. Crit Rev Toxicol. 2012 Jan;42(1):68-89 Authors: Cardinale A, Nastrucci C, Cesario A, Russo P Abstract Nowadays, tobacco smoking is the cause of ~5-6 million deaths per year, counting 31% and 6% of all cancer deaths (affecting 18 different organs) in middle-aged men and women, respectively. Nicotine is the addictive component of tobacco acting on neuronal nicotinic receptors (nAChR). Functional nAChR, are also present on endothelial, haematological and epithelial cells. Although nicotine itself is regularly not referred to as a carcinogen, there is an ongoing debate whether nicotine functions as a 'tumour promoter'. Nicotine, with its specific binding to nAChR, deregulates essential biological processes like regulation of cell proliferation, apoptosis, migration, invasion, angiogenesis, inflammation and cell-mediated immunity in a wide variety of cells including foetal (regulation of development), embryonic and adult stem cells, adult tissues as well as cancer cells. Nicotine seems involved in fundamental aspects of the biology of malignant diseases, as well as of neurodegeneration. Investigating the biological effects of nicotine may provide new tools for therapeutic interventions and for the understanding of neurodegenerative diseases and tumour biology. PMID: 22050423 [PubMed - indexed for MEDLINE] Read more... Stem cell challenges in the treatment of neurodegenerative disease. Related Articles Stem cell challenges in the treatment of neurodegenerative disease. CNS Neurosci Ther. 2012 Feb;18(2):142-8 Authors: Feng Z, Gao F Abstract Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases. PMID: 22070610 [PubMed - indexed for MEDLINE] Read more... Utilization of APPswe/PS1dE9 Transgenic Mice in Research of Alzheimer's Disease: Focus on Gene Therapy and Cell-Based Therapy Applications. Related Articles Utilization of APPswe/PS1dE9 Transgenic Mice in Research of Alzheimer's Disease: Focus on Gene Therapy and Cell-Based Therapy Applications. Int J Alzheimers Dis. 2011;2011:517160 Authors: Malm T, Koistinaho J, Kanninen K Abstract One of the most extensively used transgenic mouse model of Alzheimer's disease (AD) is APPswe/PS1dE9 mice, which over express the Swedish mutation of APP together with PS1 deleted in exon 9. These mice show increase in parenchymal A load with A plaques starting from the age of four months, glial activation, and deficits in cognitive functions at the age of 6 months demonstrated by radial arm water maze and 12-13 months seen with Morris Water Maze test. As gene transfer technology allows the delivery of DNA into target cells to achieve the expression of a protective or therapeutic protein, and stem cell transplantation may create an environment supporting neuronal functions and clearing A plaques, these therapeutic approaches alone or in combination represent potential therapeutic strategies that need to be tested in relevant animal models before testing in clinics. Here we review the current utilization of APPswe/PS1dE9 mice in testing gene transfer and cell transplantation aimed at improving the protection of the neurons against A toxicity and also reducing the brain levels of A. Both gene therapy and cell based therapy may be feasible therapeutic approaches for human AD. PMID: 22114743 [PubMed] Read more...
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Hematopoietic CC-chemokine receptor 2 (CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Related Articles Hematopoietic CC-chemokine receptor 2 (CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Mol Med. 2012;18:297-313 Authors: Naert G, Rivest S Abstract Monocytes emigrate from bone marrow, can infiltrate into brain, differentiate into microglia and clear amyloid (A) from the brain of mouse models of Alzheimer's disease (AD). Here we show that these mechanisms specifically require CC-chemokine receptor 2 (CCR2) expression in bone marrow cells (BMCs). Disease progression was exacerbated in APP(Swe)/PS1 mice (transgenic mice expressing a chimeric amyloid precursor protein [APPSwe] and human presenilin 1 [PS1]) harboring CCR2-deficient BMCs. Indeed, transplantation of CCR2-deficient BMCs enhanced the mnesic deficit and increased the amount of soluble A and expression of transforming growth factor (TGF)-1 and TGF- receptors. By contrast, transplantation of wild-type bone marrow stem cells restored memory capacities and diminished soluble A accumulation in APP(Swe)/PS1 and APP(Swe)/PS1 /CCR2/ mice. Finally, gene therapy using a lentivirus-expressing CCR2 transgene in BMCs prevented cognitive decline in this mouse model of AD. Injection of CCR2 lentiviruses restored CCR2 expression and functions in monocytes. The presence of these cells in the brain of non-irradiated APP(Swe)/PS1/CCR2/ mice supports the concept that they can be used as gene vehicles for AD. Decreased CCR2 expression in bone marrow-derived microglia may therefore play a major role in the etiology of this neurodegenerative disease. PMID: 22160221 [PubMed - indexed for MEDLINE] Read more... Adult hippocampal neurogenesis and its role in Alzheimer's disease. Related Articles Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener. 2011;6:85 Authors: Mu Y, Gage FH Abstract The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD. PMID: 22192775 [PubMed - indexed for MEDLINE] Read more... Expression of Np73 in hippocampus of APP/PS1 transgenic mice following GFP-BMSCs transplantation. Related Articles Expression of Np73 in hippocampus of APP/PS1 transgenic mice following GFP-BMSCs transplantation. Neurol Res. 2011 Dec;33(10):1109-14 Authors: Wen SR, Qi HP, Ren YJ, Liu GJ, Gong FC, Zhong H, Bi S Abstract OBJECTIVE: To study the effect of hippocampal bone marrow stromal cells (GFP-BMSCs) transplantation on spatial memory and DeltaNp73 expression in APP/PS1 transgenic mice. METHODS: Twelve APP/PS1 transgenic mice randomly received either 10 l GFP-BMSCs suspension in medium (GFP-BMSCs transplantation group) or 10 l complete medium (sham-operated group). Learning and memory function of mice in both groups were observed and tested in Morris water maze experiment at 2 weeks after surgery. Senile plaques and DeltaNp73 protein in hippocampuses were determined by immunohistochemistry and western blot at 3 weeks after surgery, respectively. RESULTS: APP/PS1 mice treated with BMSCs performed significantly better on the water maze test than those in sham-operated group (P Read more... Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of APP/Ps1 mice. Related Articles Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of APP/Ps1 mice. J Alzheimers Dis. 2012;29(1):187-200 Authors: Antequera D, Portero A, Bolos M, Orive G, Hernndez RM, Pedraz JL, Carro E Abstract Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in APP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the
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cerebral cortex from VEGF microcapsules-treated APP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated APP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of APP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD. PMID: 22232015 [PubMed - indexed for MEDLINE] Read more... Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction. Related Articles Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction. Exp Neurol. 2012 Apr;234(2):521-6 Authors: Park D, Lee HJ, Joo SS, Bae DK, Yang G, Yang YH, Lim I, Matsuo A, Tooyama I, Kim YB, Kim SU Abstract A human neural stem cell (NSC) line over-expressing human choline acetyltransferase (ChAT) gene was generated and these F3.ChAT NSCs were transplanted into the brain of rat Alzheimer disease (AD) model which was induced by application of ethylcholine mustard aziridinium ion (AF64A) that specifically denatures cholinergic nerves and thereby leads to memory deficit as a salient feature of AD. Transplantation of F3.ChAT human NSCs fully recovered the learning and memory function of AF64A animals, and induced elevated levels of acetylcholine (ACh) in cerebrospinal fluid (CSF). Transplanted F3.ChAT human NSCs were found to migrate to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and astrocytes. The present study demonstrates that brain transplantation of human NSCs over-expressing ChAT ameliorates complex learning and memory deficits in AF64A-cholinotoxin-induced AD rat model. PMID: 22245157 [PubMed - indexed for MEDLINE] Read more... Neurosteroid PREGS protects neurite growth and survival of newborn neurons in the hippocampal dentate gyrus of APPswe/PS1dE9 mice. Related Articles Neurosteroid PREGS protects neurite growth and survival of newborn neurons in the hippocampal dentate gyrus of APPswe/PS1dE9 mice. Curr Alzheimer Res. 2012 Mar;9(3):361-72 Authors: Xu B, Yang R, Chang F, Chen L, Xie G, Sokabe M, Chen L Abstract Neurosteroids pregnenolone-sulfate (PREGS) and dehydroepiandrosterone (DHEA) have been shown to enhance neurogenesis in the hippocampal dentate gyrus (DG) of adult rodents. In Alzheimer's disease (AD) brain, the levels of these neurosteroids are known to be altered compared to age-matched non-demented controls. The aim of this study was to examine the effects of PREGS and DHEA on the hippocampal neurogenesis in 8-month-old male APPswe/PS1dE9 transgenic (APP/PS1) mice that show amyloid plaques and impaired spatial cognitive performance. In the DG of APP/PS1 mice the proliferation of progenitor cells was increased, while the neurite growth and survival of newborn neuronal cells were markedly impaired. Treatment with PREGS or DHEA rescued perfectly the hypoplastic neurite of newborn neurons in APP/PS1 mice, while neither of them affected the over-proliferation of progenitor cells. Notably, the administration of PREGS, but not DHEA, to APP/PS1 mice could protect the survival and maturation of newborn neuronal cells, which was accompanied by the improvement of spatial cognitive performance. The results indicate that treatment of AD like brains of APP/PS1 mice with PREGS might protect the hippocampal neurogenesis, leading to the improved spatial cognitive performance. PMID: 22272612 [PubMed - indexed for MEDLINE] Read more... Low-dose radiation stimulates Wnt/-catenin signaling, neural stem cell proliferation and neurogenesis of the mouse hippocampus in vitro and in vivo. Related Articles Low-dose radiation stimulates Wnt/-catenin signaling, neural stem cell proliferation and neurogenesis of the mouse hippocampus in vitro and in vivo. Curr Alzheimer Res. 2012 Mar;9(3):278-89 Authors: Wei LC, Ding YX, Liu YH, Duan L, Bai Y, Shi M, Chen LW Abstract Neurogenesis in the hippocampus is actively involved in neural circuit plasticity and learning function of mammals, but it may decrease dramatically with aging and aging-related neurodegenerative disorder Alzheimer's disease. Accumulating studies have indicated that Wnt/-catenin signaling is critical in control of proliferation and differentiation fate of neural stem cells or progenitors in the hippocampus. In this study, the biological effects of low-dose radiation in stimulating Wnt/-catenin signaling, neural stem cell proliferation
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and neurogenesis of hippocampus were interestingly identified by in vitro cell culture and in vivo animal studies. First, low-dose radiation (0.3Gy) induced significant increasing of Wnt1, Wnt3a, Wnt5a, and -catenin expression in both neural stem cells and in situ hippocampus by immunohistochemical and PCR detection. Secondly, low-dose radiation enhanced the neurogenesis of hippocampus indicated by increasing proliferation and neuronal differentiation of neural stem cells, going up of nestin-expressing cells and BrdU-incorporation in hippocampus. Thirdly, it promoted cell survival and reduced apoptotic death of neuronal stem cells by flowcytometry analysis. Finally, Morris water-maze test showed behavioral improvement of animal learning in low-dose radiation group. Accordingly, detrimental influence on Wnt/catenin signaling or neurogenesis was confirmed in high-dose radiation (3.0Gy) group. Taken together, this study has revealed certain beneficial effects of low-dose radiation to stimulate neural stem cell proliferation, the neurogenesis of hippocampus and animal learning most possibly by triggering Wnt/-catenin signaling cascades, suggesting its translational application role in devising new therapy for aging-related neurodegenerative disorders particularly Alzheimer's disease. PMID: 22272614 [PubMed - indexed for MEDLINE] Read more... Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Related Articles Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012 Feb 9;482(7384):216-20 Authors: Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS Abstract Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid- precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescenceactivated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3 (aGSK-3). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with -secretase inhibitors, but not -secretase inhibitors, caused significant reductions in phospho-Tau(Thr231) and aGSK-3 levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-, in GSK-3 activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients. PMID: 22278060 [PubMed - indexed for MEDLINE] Read more... Stem cell therapy in treatment of different diseases. Related Articles Stem cell therapy in treatment of different diseases. Acta Med Iran. 2012;50(2):79-96 Authors: Larijani B, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S, Malekzadeh R, Yazdi NM, Ghodsi M, Dowlati Y, Sahraian MA, Ghavamzadeh A Abstract Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia). In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article. PMID: 22359076 [PubMed - indexed for MEDLINE] Read more... [Stem cell-based treatment of neurologic diseases]. Related Articles [Stem cell-based treatment of neurologic diseases]. Med Clin (Barc). 2012 Jul 21;139(5):208-14 Authors: Costa C, Comabella M, Montalban X Abstract Therapeutic strategies based on stem cells are being
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increasingly used to treat a wide range of neurological diseases. Although these strategies were initially designed to replace dead cells in injured tissue, the potential of stem cells to migrate, secrete trophic factors, and immunomodulate allows their therapeutic use as a vehicle for gene therapy, as in Parkinson's disease, or as immunomodulators and neuroprotectors in diseases such as multiple sclerosis. This review will focus on current clinical and experimental evidence on the treatment of neurological disorders with strategies based on stem cells. PMID: 22361347 [PubMed indexed for MEDLINE] Read more... [Bioethics, miscellaneous]. Related Articles [Bioethics, miscellaneous]. Rev Med Suisse. 2011 Nov 23;7(318):2318-9 Authors: Nau JY PMID: 22400372 [PubMed - indexed for MEDLINE] Read more... Therapeutic effects of human amniotic epithelial cell transplantation on double-transgenic mice co-expressing APPswe and PS1E9-deleted genes. Related Articles Therapeutic effects of human amniotic epithelial cell transplantation on double-transgenic mice co-expressing APPswe and PS1E9-deleted genes. Sci China Life Sci. 2012 Feb;55(2):132-40 Authors: Xue S, Chen C, Dong W, Hui G, Liu T, Guo L Abstract Human amniotic epithelial cells (HAECs), which exhibit characteristics of embryonic and pluripotent stem cells, could be utilized for cell therapy without legal or ethical problems. Doubletransgenic (TG) mice (n=20) and wild-type (WT) mice (n=20) were randomly assigned to two groups, respectively. The transplantation group was treated with HAECs and the control group with PBS. A six-radial arm water maze was used to assess spatial memory. Immunofluorescence was utilized to track HAEC survival. Immunohistochemistry was used to determine octamer-binding protein 4 (oct-4) and nanog expression in the HAECs. High-performance liquid chromatography (HPLC) was used to measure acetylcholine levels in the hippocampus. The density of cholinergic neurons in the basal forebrain and nerve fibers in the hippocampus was measured following acetylcholinesterase staining. Results showed that transplanted HAECs survived for at least eight weeks and migrated to the third ventricle without immune rejection. Graft HAECs also expressed the specific stem cell markers oct-4 and nanog. Compared with the control group, HAEC transplantation significantly ameliorated spatial memory deficits in TG mice, as well as increased acetylcholine levels and the number of hippocampal cholinergic neurites. Intracerebroventricular HAEC transplantation improved spatial memory in double-TG mice, and results suggested that increased acetylcholine levels in the hippocampus, released by surviving cholinergic neurites, were responsible for this improvement. PMID: 22415684 [PubMed - indexed for MEDLINE] Read more... Chemical analysis and acetylcholinesterase inhibitory effect of anthocyanin-rich red leaf tea (cv. Sunrouge). Related Articles Chemical analysis and acetylcholinesterase inhibitory effect of anthocyanin-rich red leaf tea (cv. Sunrouge). J Sci Food Agric. 2012 Aug 30;92(11):2379-86 Authors: Maeda-Yamamoto M, Saito T, Nesumi A, Tokuda Y, Ema K, Honma D, Ogino A, Monobe M, Murakami A, Murakami A, Tachibana H Abstract BACKGROUND: The purpose of this study was to evaluate the effects of leaf order or crop season on anthocyanins and other chemicals in the anthocyanin-rich tea cultivar 'Sunrouge' (Camellia sinensis x C. taliensis) by using high-performance liquid chromatography, and to study the effect of 'Sunrouge' extract on acetylcholinesterase (AChE) activity in human neuroblastoma SK-N-SH cells. RESULTS: The total anthocyanin content was higher in the third (3.09 mg g) than in the second (2.24 mg g) or first crop season (1.79 mg g). The amount of anthocyanins contained in the stem was high (1.61 mg g). In the third crop season, the concentrations of delphinidin-3-O--D-(6-(E)-pcoumaroyl)galactopyranoside (DCGa), cyanidin-3-O--D-(6-(E)-p-coumaroyl)galactopyranoside, delphinidin-3-O-D-galactopyranoside, delphinidin-3-O--D-(6-O-(Z)-p-coumaroyl)galactopyranoside, cyanidin-3-O--D-galactoside, and delphinidin-3-O--D-glucoside were 1.57 mg g, 0.52 mg g, 0.40 mg g, 0.22 mg g, 0.14 mg g, and 0.11 mg g, respectively. DCGa accounted for about 50% of the anthocyanins present. The suppressive effect of 'Sunrouge' water extract on AChE activity in human neuroblastoma SK-N-SH cells was the strongest among the three tea cultivars ('Sunrouge', 'Yabukita' and 'Benifuuki'). CONCLUSION: These results suggested that 'Sunrouge' might protect humans from humans from AChE-related diseases by suppressing AChE activity. To obtain sufficient amounts of anthocyanins, catechins and/or caffeine for a functional food material, 'Sunrouge' from the third crop season should be used. PMID: 22419270 [PubMed - indexed for MEDLINE] Read more...
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Delivery of epidermal neural crest stem cells (EPI-NCSC) to hippocamp in Alzheimer's disease rat model. Related Articles Delivery of epidermal neural crest stem cells (EPI-NCSC) to hippocamp in Alzheimer's disease rat model. Iran Biomed J. 2012;16(1):1-9 Authors: Esmaeilzade B, Nobakht M, Joghataei MT, Rahbar Roshandel N, Rasouli H, Samadi Kuchaksaraei A, Hosseini SM, Najafzade N, Asalgoo S, Hejazian LB, Moghani Ghoroghi F Abstract BACKGROUND: Alzheimer's disease (AD) is characterized by progressive neuronal loss in hippocamp. Epidermal neural crest stem cells (EPI-NCSC) can differentiate into neurons, astrocytes and oligodendrocytes. The purpose of this study was to evaluate the effects of transplanting EPI-NCSC into AD rat model. METHODS: Two weeks after induction of AD by injection of Amyloid-1-40 into CA1 area of rat hippocamp, Y-maze and single-trial passive avoidance tests were used to show deficit of learning and memory abilities. EPI-NCSC were obtained from the vibrissa hair follicle of rat, cultured and labeled with bromodeoxyuridine. When Alzheimer was proved by behavioral tests, EPI-NCSC was transplanted into CA3 area of hippocamp in AD rat model. The staining of EPI-NCSC markers (nestin and SOX10) was done in vitro. Double-labeling immunofluorescence was performed to study survival and differentiation of the grafted cells. RESULTS: We showed that transplanted EPI-NCSC survive and produce many neurons and a few glial cells, presenting glial fibrillary acidic protein. Total number of granule cells in hippocamp was estimated to be more in the AD rat model with transplanted cells as compared to AD control group. We observed that rats with hippocampal damage made more errors than control rats on the Y-maze, when reward locations were reversed. CONCLUSION: Transplanted cells were migrated to all areas of hippocamp and the total number of granule cell in treatment group was equal compared to control group. Transplantation of EPI-NCSC into hippocamp might differentiate into cholinergic neurons and could cure impairment of memory in AD rat model. PMID: 22562026 [PubMed - indexed for MEDLINE] Read more... Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA. Related Articles Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA. Neuroreport. 2012 Jul 11;23(10):621-6 Authors: Lukiw WJ, Alexandrov PN, Zhao Y, Hill JM, Bhattacharjee S Abstract Alzheimer's disease is a progressive, neurodegenerative disorder that develops within the limbic system, spreading radially into anatomically linked brain association areas as the disease progresses. Analysis of temporal-lobe association of neocortex-derived extracellular fluid and cerebrospinal fluid from Alzheimer's disease patients shows an abundant presence of micro-RNA (miRNA), including the proinflammatory miRNA-146a and miRNA-155. Using a novel and highly sensitive LED-Northern dot-blot focusing technique, we detected the secretion of potentially pathogenic amounts of miRNA-146a and miRNA-155 from stressed human primary neural cells. A conditioned medium containing miRNA-146a and miRNA-155 was found to induce Alzheimer-type gene expression changes in control brain cells. These included downregulation in the expression of an important repressor of the innate immune response, complement factor H (CFH). These effects were neutralized using anti-miRNA strategies. Anti-miRNA-based therapeutics may provide a novel and efficacious treatment to stem the miRNA-mediated spreading of inflammatory signaling involved in Alzheimer's disease. PMID: 22660168 [PubMed - indexed for MEDLINE] Read more... Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer's disease. Related Articles Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer's disease. J Neural Transm. 2013 Jan;120(1):103-11 Authors: Ooi L, Sidhu K, Poljak A, Sutherland G, O'Connor MD, Sachdev P, Mnch G Abstract Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person's memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of -amyloid (A), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, early-onset form of AD, controversy exists between the "Baptists" (in favour of A) and the "Tauists" (in favour of tau) as to which of these two protein dysfunctions occur at the earliest stages or are the most important contributors to the disease process in sporadic AD. However, more and more "non-amyloid" and "non-tau" causes have been proposed, including, glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. However, to get an insight into the ultimate cause of AD, and to prove that any drug target is valuable in AD, disease-relevant models giving insight into the pathogenic processes in AD are urgently needed. In the absence of a good animal model for sporadic AD, we propose in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD. PMID: 22695755 [PubMed -
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indexed for MEDLINE] Read more... Pilot study of granulocyte-colony stimulating factor for treatment of Alzheimer's disease. Related Articles Pilot study of granulocyte-colony stimulating factor for treatment of Alzheimer's disease. J Alzheimers Dis. 2012;31(4):843-55 Authors: Sanchez-Ramos J, Cimino C, Avila R, Rowe A, Chen R, Whelan G, Lin X, Cao C, Ashok R Abstract Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance. PMID: 22751169 [PubMed - indexed for MEDLINE] Read more... Recent preclinical evidence advancing cell therapy for Alzheimer's disease. Related Articles Recent preclinical evidence advancing cell therapy for Alzheimer's disease. Exp Neurol. 2012 Sep;237(1):142-6 Authors: Borlongan CV Abstract Alzheimer's disease (AD) causes brain degeneration, primarily depleting cholinergic cells, and leading to cognitive and learning dysfunction. Logically, to augment the cholinergic cell loss, a viable treatment for AD has been via drugs boosting brain acetylcholine production. However, this is not a curative measure. To this end, nerve growth factor (NGF) has been examined as a possible preventative treatment against cholinergic neuronal death while enhancing memory capabilities; however, NGF brain bioavailability is challenging as it does not cross the blood-brain barrier. Investigations into stem cell- and gene-based therapy have been explored in order to enhance NGF potency in the brain. Along this line of research, a genetically modified cell line, called HB1.F3 transfected with the cholinergic acetyltransferase or HB1.F3.ChAT cells, has shown safety and efficacy profiles in AD models. This stem cell transplant therapy for AD is an extension of the neural stem cells' use in other neurological treatments, such as Parkinson's disease and stroke, and recently extended to cancer. The HB1 parent cell and its associated cell lines have been used as a vehicle to deliver genes of interest in various neurological models, and are highly effective as they can differentiate into neurons and glial cells. A focus of this mini-review is the recent demonstration that the transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive function coinciding with upregulation of acetylcholine levels in the cerebrospinal fluid. In addition, there is a large dispersion throughout the brain of the transplanted stem cells which is important to repair the widespread cholinergic cell loss in AD. Some translational caveats that need to be satisfied prior to initiating clinical trials of HB1.F3.ChAT cells in AD include regulating the host immune response and the possible tumorigenesis arising from the transplantation of this genetically modified cell line. Further studies are warranted to test the safety and effectiveness of these cells in AD transgenic animal models. This review highlights the recent progress of stem cell therapy in AD, not only emphasizing the significant basic science strides made in this field, but also providing caution on remaining translational issues necessary to advance this novel treatment to the clinic. PMID: 22766481 [PubMed - indexed for MEDLINE] Read more... Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid--associated neuropathology in Alzheimer mice. Related Articles Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid--associated neuropathology in Alzheimer mice. Stem Cells Dev. 2013 Feb 1;22(3):412-21 Authors: Darlington D, Deng J, Giunta B, Hou H, Sanberg CD, Kuzmin-Nichols N, Zhou HD, Mori T, Ehrhart J, Sanberg PR, Tan J Abstract Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of
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-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid- (A) levels/-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (110(6) cells/L) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) A levels/-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level. PMID: 22816379 [PubMed - indexed for MEDLINE] Read more... Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Related Articles Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol Pharm Bull. 2012;35(8):1206-12 Authors: Fukasawa H, Nakagomi M, Yamagata N, Katsuki H, Kawahara K, Kitaoka K, Miki T, Shudo K Abstract Tamibarotene (Am80), a synthetic retinoid approved in Japan for treatment of acute promyelocytic leukemia (APL), is a retinoic acid receptor (RAR) agonist with high specificity for RAR and RAR over RAR. Temporarily and spatially specific expression of RARs suggests their pivotal roles in the adult brain. Am80 is considered to be a promising candidate drug for treatment of Alzheimer's disease (AD) because of its transcriptional controls of multiple target genes involved in etiology and pathology of AD. In APP23 AD model mice, administration of Am80 decreased the deposition of insoluble amyloid-(42). In senescence-accelerated mice (SAMP8), Am80 ameliorated the decrease of cortical acetylcholine, as well as reducing anxiety in behavioral tests and improving the sleep deficit. Am80 also effected a significant improvement of memory in the rat scopolamine-induced memory deficit model. Like other retinoids, Am80 also has an immunomodulatory effect and reduces secretion of proinflammatory cytokines and chemokines by astrocytes and microglia surrounding amyloid- plaques. In a rat experimental autoimmune encephalomyelitis model, Am80 reduced inflammatory cytokines and showed significant efficacy. Retinoids also promote differentiation of neural stem cells, and Am80 improved the recovery of spinal cord-injured rats. Am80 may also improve vascular factors involved in onset and/or progression of AD. Am80 has been in clinical use for treatment of APL in Japan since 2005, and has been reported to have fewer side effects than other retinoids. We have recently started a clinical study to evaluate the efficacy and safety of Am80 for the treatment of Alzheimer's disease. PMID: 22863914 [PubMed - indexed for MEDLINE] Read more... Alzheimer's disease in a dish: promises and challenges of human stem cell models. Related Articles Alzheimer's disease in a dish: promises and challenges of human stem cell models. Hum Mol Genet. 2012 Oct 15;21(R1):R82-9 Authors: Young JE, Goldstein LS Abstract Human pluripotent stem cells can differentiate into disease-relevant cell types, which capture the unique genome of an individual patient and provide insight into pathological mechanisms of human disease. Recently, human stem cell models for Alzheimer's disease (AD), the most common neurodegenerative dementia, have been described. Stem cell-derived neurons from patients with familial and sporadic AD and Down's syndrome recapitulate human disease phenotypes such as amyloid peptide production, hyperphosphorylation of tau protein and endosomal abnormalities. Treatment of human neurons with small molecules can modulate these phenotypes, demonstrating the utility of this system for drug development and screening. This review will highlight the current AD stem cell models and discuss the remaining challenges and potential future directions of this field. PMID: 22865875 [PubMed - indexed for MEDLINE] Read more... Effect of magnetic stimulation on the gene expression profile of in vitro cultured neural cells. Related Articles Effect of magnetic stimulation on the gene expression profile of in vitro cultured neural cells. Neurosci Lett. 2012 Sep 27;526(2):122-7 Authors: Stock M, Kirchner B, Waibler D, Cowley DE, Pfaffl MW, Kuehn R Abstract Transcranial magnetic stimulation is a non-invasive tool in clinical diagnostics and therapy for physiological and psychological diseases and has an increased application in experimental neurophysiology. Despite this, the mechanisms of magnetic stimulation of the central nervous system remain still unclear. We applied sinus-shaped high frequency magnetic fields in different stimulation patterns and repeated treatments to cell cultures derived from frontal cortex of murine embryos (BALB/cOlaHsd mice) to elucidate the effects of repetitive magnetic stimulation on the gene
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expression of in vitro cultured neural cells. Gene expression profiling was performed by using qRT-PCR array and single qRT-PCR analyses. Our methodological approach using microelectrode arrays data recording and analysis minimizes variations in transcriptome analysis arising from cell differentiation status and tissue complexity. With 10 significant changes in gene expression out of 171 genes using Alzheimer disease and neurodegeneration related qRT-PCR arrays we demonstrate significant impact of repetitive magnetic stimulation on the mRNA transcript of neural cell cultures. Sixteen candidate genes were analyzed using single qRT-PCR in a replicated statistical design, which provided more precise estimates of differences in expression profiles. We discussed the utility of the experimental methods used for cell culture selection and the changes in gene expression considering physiological aspects. PMID: 22925660 [PubMed - indexed for MEDLINE] Read more... Therapeutic gene products delivery by neuron stem cells. Related Articles Therapeutic gene products delivery by neuron stem cells. Curr Pharm Biotechnol. 2012 Sep;13(12):2427-31 Authors: Tan J, Meng Y, Huang S, Wang P Abstract Malignant tumors remain virtually untreatable and inevitably lethal despite extensive surgical excision and adjuvant radio- and chemotherapy. Therefore, the development of more effective tumor-selective therapies is necessary. Stem/progenitor cells that self-renew, differentiate and display inherent tumor-tropic properties can be exploited for targeted delivery of therapeutic genes to invasive and metastatic tumors. In this review, we mainly introduce the application in Glioma, Breast cancer, Spinal cord injury, AD and so on. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research. PMID: 23016647 [PubMed - indexed for MEDLINE] Read more... Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid- deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease. Related Articles Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid- deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease. Curr Alzheimer Res. 2013 Jun;10(5):524-31 Authors: Bae JS, Jin HK, Lee JK, Richardson JC, Carter JE Abstract The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on -amyloid (A) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral A deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in A deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD. PMID: 23036020 [PubMed - in process] Read more... Clioquinol-induced increase and decrease in the intracellular Zn2+ level in rat thymocytes. Related Articles Clioquinol-induced increase and decrease in the intracellular Zn2+ level in rat thymocytes. Life Sci. 2012 Dec 10;91(23-24):1216-20 Authors: Oyama TM, Ishida S, Okano Y, Seo H, Oyama Y Abstract AIMS: Clioquinol is emerging as a potential therapy for some diseases, such as Alzheimer disease and cancer. This agent is a lipophilic chelator of Zn(2+). In this study, the effect of clioquinol on the intracellular Zn(2+) level was examined in order to gain insights into the toxicological profile of clioquinol. MAIN METHODS: The effect of clioquinol was estimated using a flow cytometer and FluoZin-3, a fluorescent indicator for Zn(2+), in rat thymocytes. KEY FINDINGS: Clioquinol, at concentrations ranging from 10 to 300 nM, augmented FluoZin-3 fluorescence in a concentration-dependent manner. However, the effect induced by 1 M clioquinol was less than that by 300 nM clioquinol. Removal of extracellular Zn(2+), using the membrane impermeable Zn(2+)-chelator diethylenetriamine-N,N,N',N,N-pentaacetic acid (DTPA), abolished the clioquinol-induced augmentation of FluoZin-3 fluorescence. Clioquinol did not augment Fluo-3
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fluorescence, an indicator of intracellular Ca(2+), in the presence of DTPA. The results suggested that clioquinol caused an extracellular Zn(2+)-dependent increase in the intracellular Zn(2+) concentration. However, in the presence of DTPA, clioquinol at micromolar concentrations (1-10 M) attenuated FluoZin-3 fluorescence in a concentrationdependent manner. Clioquinol even at 10 M did not affect FluoZin-3 fluorescence under cell-free condition. The concentration-response relationship for the clioquinol induced change in Zn(2+) level appeared to be bell-shaped. These results indicate that micromolar concentrations of clioquinol, without chelated Zn(2+), decrease intracellular Zn(2+) concentration. SIGNIFICANCE: The effect of clioquinol on the intracellular Zn(2+) level varies, depending on the extracellular Zn(2+) concentration and the clioquinol concentration. Clioquinol may therefore exert various types of Zn(2+)-dependent cytotoxicity. PMID: 23044228 [PubMed - indexed for MEDLINE] Read more... The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice. Related Articles The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice. PLoS One. 2012;7(9):e45757 Authors: Kim S, Chang KA, Kim Ja, Park HG, Ra JC, Kim HS, Suh YH Abstract Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques and neurofibrillary tangles accompanied by cognitive dysfunction. The aim of the present study was to elucidate preventive and therapeutic potential of stem cells for AD. Among stem cells, autologous human adipose-derived stem cells (hASCs) elicit no immune rejection responses, tumorigenesis, or ethical problems. We found that intravenously transplanted hASCs passed through the BBB and migrated into the brain. The learning, memory and pathology in an AD mouse model (Tg2576) mice greatly improved for at least 4 months after intravenous injection of hASC. The number of amyloid plaques and A levels decreased significantly in the brains of hASC-injected Tg mice compared to those of Tg-sham mice. Here, we first report that intravenously or intracerebrally transplanted hASCs significantly rescues memory deficit and neuropathology, in the brains of Tg mice by up-regulating IL-10 and VEGF and be a possible use for the prevention and treatment of AD. PMID: 23049854 [PubMed - indexed for MEDLINE] Read more... Prazosin, an (1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease. Related Articles Prazosin, an (1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2013 Apr;34(4):1105-15 Authors: Katsouri L, Vizcaychipi MP, McArthur S, Harrison I, Surez-Calvet M, Lleo A, Lloyd DG, Ma D, Sastre M Abstract Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an (1)-adrenoceptor antagonist, was able to reduce the generation of amyloid in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance. PMID: 23063647 [PubMed - indexed for MEDLINE] Read more... Investigation of the performance of PEG-PEI/ROCK-II-siRNA complexes for Alzheimer's disease in vitro. Related Articles Investigation of the performance of PEG-PEI/ROCK-II-siRNA complexes for Alzheimer's disease in vitro. Brain Res. 2013 Jan 15;1490:43-51 Authors: Liu Y, Liu Z, Wang Y, Liang YR, Wen X, Hu J, Yang X, Liu J, Xiao S, Cheng D Abstract Recent studies have showed inhibiting ROCK promoted axonal regeneration and suppressing ROCK-II decreased A formation, suggesting ROCK is a potential target for the treatment of Alzheimer's disease. Because ROCK-II mRNA is abundantly expressed in brain, we targeted ROCK-II mRNA using a siRNA approach. To suppress ROCK-II mRNA expression, we synthesized PEG-PEI/ROCK-II-siRNA complexes and transfected C17.2 neural stem cells in vitro. The characteristics of the complexes were tested using a gel retardation assay. Particle size and zeta potential were examined using dynamic light scattering and the morphology of the complexes were observed by transmission electron microscopy. The toxicity was detected by an MTT assay and transfection efficiency was determined by flow cytometry. Laser confocal microscopy was employed to investigate the cell uptake of the complexes. RT-PCR and western blotting were used to verify the effect of gene silencing. Our results indicated that the
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characteristics of the complexes depended on the N/P ratios. At a high N/P ratio, PEG-PEI could completely condense the siRNA into small-sized uniform particles. However, high N/P ratios are accompanied with high cytotoxicity. Because of high transfection efficiency and low cytotoxicity, N/P=50 was chosen to transfect C17.2 cells in vitro. Laser confocal microscopy showed that ROCK-II-siRNA with green fluorescence was mainly distributed in the cytoplasm and synapses. Moreover, ROCK-II-siRNA was successfully released from the lysosome. RT-PCR and western blotting demonstrated effective gene silencing. These results indicated that PEG-PEI/ROCK-II-siRNA complexes effectively suppressed ROCK-II mRNA expression, providing the basis for future research in vivo. PMID: 23103413 [PubMed indexed for MEDLINE] Read more... Current therapeutic strategy in Alzheimer's disease. Related Articles Current therapeutic strategy in Alzheimer's disease. Eur Rev Med Pharmacol Sci. 2012 Nov;16(12):1651-64 Authors: Singh S, Kushwah AS, Singh R, Farswan M, Kaur R Abstract Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disorder that places a substantial burden on patients, their families, and society. Alzheimer's disease (AD) is the sixth leading cause of all deaths in the United States, and the fifth leading cause of death in Americans aged 65 and older. During the past years, several agents have been approved that enhance cognition and global function of AD patients, and recent advances in understanding AD pathogenesis has led to the development of numerous compounds that might modify the disease process. A wide array of antiamyloid and neuroprotective therapeutic approaches are under investigation on the basis of the hypothesis that amyloid beta (A) protein plays a pivotal role in disease onset and progression and that secondary consequences of A generation and deposition, including tau hyperphosphorylation and neurofibrillary tangle formation, oxidation, inflammation, and excitotoxicity, contribute to the disease process. Interventions in these processes with agents that reduce amyloid production, limit aggregation, or increase removal or vaccination and immunization might block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation might be beneficial disease-modifying strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell-related approaches are also under investigation. PMID: 23161037 [PubMed - indexed for MEDLINE] Read more... [Migration of PKH26-labeled mesenchymal stem cells in rats with Alzheimer's disease]. Related Articles [Migration of PKH26-labeled mesenchymal stem cells in rats with Alzheimer's disease]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2012 Nov;41(6):659-64 Authors: Li WY, Jin RL, Hu XY Abstract OBJECTIVE: To investigate the migration of fluorescent dye PKH26-labeled BM-MSC in the Alzheimer's model rats. METHODS: Normal human bone marrow extracted for isolation of BM-MSC was cultured in vitro. The 5th passaged BM-MSC was labeled with PKH26, and observed under a fluorescence microscope for PKH26 labeling efficiency, and using flow cytometry BM-MSC surface markers was checked. The PKH26 labeled BM-MSC injected into the tail vein of the normal control group and AD animal model group, 14 days after finding the PKH26-labeled BM-MSC cells in the rat hippocampus using fluorescence microscopy. Using the Morris water maze experiment comparison of AD model and BM-MSC transplantation group of spatial learning and memory ability. RESULTS: TFlow cytometry showed BM-MSC surface markers CD73 and CD105 were positive. In vitro, PKH26-labeled rate of BM-MSC was 100 %. The Morris water maze experiment comparison of BM-MSC transplantation group and AD group of animals, BM-MSC transplantation group at 13, 14 days of spatial learning and memory ability than AD animal group had significantly improved. 14 days after BM-MSCs in rat hippocampus could be found which were PKH26-positive, consistent with DAPI staining. PKH26positive cells in animal models of AD were significantly more than those in the normal control group. CONCLUSION: BM-MSC in AD rats not only migrates through the blood-brain barrier, but also mainly survives in the hippocampus of AD rats, and it can improve AD rat model of learning disabilities. PMID: 23239658 [PubMed - indexed for MEDLINE] Read more... Intrahippocampal injection of A1-42 inhibits neurogenesis and down-regulates IFN- and NF-B expression in hippocampus of adult mouse brain. Related Articles Intrahippocampal injection of A1-42 inhibits neurogenesis and down-regulates IFN- and NF-B expression in hippocampus of adult mouse brain. Amyloid. 2013 Mar;20(1):13-20 Authors: Zheng M, Liu J, Ruan Z, Tian S, Ma Y, Zhu J, Li G Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid- (A) is widely recognized as a key factor in the pathogenesis of AD. A1-42 a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. Alteration of neurogenesis in AD patients has been reported,
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while little is known about how A1-42 affects hippocampal neurogenesis in the adult brain. In this study, we injected human A1-42 peptide into hippocampal CA1 area of adult mouse brain bilaterally and evaluated histological change and neurogenesis in the hippocampus. Hematoxylin and eosin (HE) stain showed that A1-42-injection resulted in an extensive neurodegeneration in the A-accumulated area and CA3 in hippocampus. Immunostaining showed that intrahippocampal A1-42-injection dramatically decreased the number of bromodeoxyuridine (BrdU)-positive cells in the dentate gyrus (DG) compared to the vehicle injection. Moreover, a significant decrease in the number of BrdU/double-cortin double-positive cells in A1-42-injected hippocampus was observed, suggesting that A1-42injection inhibited progenitor cell proliferation and neurogenesis in subgranular zone of the DG in the adult brain. We also found that the A1-42-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon- (IFN-) and transcription factor nuclear factor-kappa B (NF-B) in the hippocampus. These results suggest that A1-42 inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF- and NF-B signaling pathway. This study provides a new insight into A1-42-mediated decrease in hippocampal neurogenesis in the adult central nervous system. PMID: 23286786 [PubMed - indexed for MEDLINE] Read more... Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. Related Articles Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One. 2013;8(1):e54887 Authors: Lilja AM, Luo Y, Yu QS, Rjdner J, Li Y, Marini AM, Marutle A, Nordberg A, Greig NH Abstract Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid- peptide (A) and a loss of trophic factor support. Amelioration of these was assessed with the A lowering AD experimental drugs (+)-phenserine and (-)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of A and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserineinduced elevation in brain- derived neurotrophic factor (BDNF). PMID: 23382994 [PubMed - indexed for MEDLINE] Read more... Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an APP/PS1 transgenic mouse model. Related Articles Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an APP/PS1 transgenic mouse model. Stem Cell Res Ther. 2013 Jul 4;4(4):76 Authors: Yang H, Xie Z, Wei L, Yang H, Yang S, Zhu Z, Wang P, Zhao C, Bi J Abstract INTRODUCTION: Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined. METHODS: In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an APP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid -peptides (A) deposition, and microglial function of the mice were investigated. RESULTS: We found that transplantation of HUMSC-NCs into APP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced A deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1 (IL-1) and tumor necrosis factor- (TNF-), was significantly reduced. Moreover, the expression of A-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs. CONCLUSIONS: HUMSC-NC transplantation decreased A
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deposition and improved memory in APP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease. PMID: 23826983 [PubMed - as supplied by publisher] Read more... Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer's disease mice. Related Articles Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer's disease mice. Brain Res. 2013 Sep 5;1529:113-24 Authors: Park MH, Lee JK, Choi S, Ahn J, Jin HK, Park JS, Bae JS Abstract Accumulation of amyloid- (A) is thought to be a central pathology in the brain of patients with Alzheimer's disease (AD). Neprilysin (NEP), a plasma membrane glycoprotein of the neutral zinc metalloendopeptidase family, is known as a major A-degrading enzyme in the brain. The level of NEP is reduced in the brains of patients with AD; therefore, NEP is under intense investigation as a potential therapeutic source for degradation of deposited A in AD. Previous studies have utilized viral vectors expressing NEP for reduction of A deposition in the brain. However, viral vectors have disadvantages regarding difficulty in control of insert size, expression desired (short- or long-term), and target cell type. Here, in order to overcome these disadvantages, we produced recombinant soluble NEP from insect cells using an NEP expression vector, which was administered by intracerebral injection into AD mice, resulting in significantly reduced accumulation of A. In addition, AD mice treated with NEP showed improved behavioral performance on the water maze test. These data support a role of recombinant soluble NEP in improving memory impairment by regulation of A deposition and suggest the possibility that approaches using protein therapy might have potential for development of alternative therapies for treatment of AD. PMID: 23831521 [PubMed - in process] Read more... Distinct Roles of sAPP- and sAPP- in Regulating U251 Cell Differentiation. Related Articles Distinct Roles of sAPP- and sAPP- in Regulating U251 Cell Differentiation. Curr Alzheimer Res. 2013 Sep;10(7):706-13 Authors: Jiang J, Wang Y, Hou L, Fan L, Wang Q, Xu Z, Sun Q, Liu H Abstract Sequential cleavages of APP by -secretase and -secretase release -amyloid (A) and one secreted form of APP (sAPP-) in Alzheimer' s disease (AD). Alternatively, in non-pathological situations, APP is predominantly cleaved by -secretase within the amyloid sequence, to release the other soluble form of APP, sAPP-. However, the functions of the two types of sAPP are still unclear. We performed this study to compare the function of sAPP- and sAPP- in differentiation of the glioma cell line U251. We found that sAPP- suppressed astrocytic differentiation and promoted neuronal differentiation in U251 cells. Additionally, sAPP- enhanced U251 terminal differentiation into a cholinergic-like neuronal phenotype. In contrast, sAPP- suppressed neuronal differentiation and promoted the astrocytic differentiation of U251 cells. These findings could not only enrich the knowledge of the potential physiological function of sAPP- and sAPP-, but also indicate that they may be connected to the pathological mechanism of AD. Furthermore, these findings suggest that new strategies, such as increasing the level of sAPP- and/or decreasing the level of sAPP- in brain, or transplanting stem cells with increased sAPP- and/or decreased sAPP-, may have potential value for AD treatment. PMID: 23905992 [PubMed - in process] Read more... Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer 's disease. Related Articles Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer 's disease. Neuropharmacology. 2013 Aug 21; Authors: McClean PL, Hlscher C Abstract Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1E9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-Month-old APP/PS1 and littermate control mice were injected with Liraglutide (25nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced
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in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutidetreated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. PMID: 23973293 [PubMed - as supplied by publisher] Read more...
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Stem Cell Treatment Alzheimer&#39;s Disease - ASCI - Asian Stem Cell Institute

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Stem Cell Treatment Alzheimer&#39;s Disease - ASCI - Asian Stem Cell Institute

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Stem Cell Treatment Alzheimer's Disease - ASCI - Asian Stem ...