You are on page 1of 13

Int. J. Mol. Sci. 2014, 15, 19226-19238; doi:10.

3390/ijms151019226
OPEN ACCESS

International Journal of

Molecular Sciences
ISSN 1422-0067
www.mdpi.com/journal/ijms
Review

Stem Cell Treatment for Alzheimer’s Disease
Ming Li 1, Kequan Guo 2 and Susumu Ikehara 1,*
1

2

Department of Stem Cell Disorders, Kansai Medical University, 2-5-1 Shinmachi, Hirakata City,
Osaka 573-1010, Japan; E-Mail: liming@hirakata.kmu.ac.jp
Department of Cardiac Surgery, Beijing Institute of Heart, Lung & Blood Vessel Disease,
Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China;
E-Mail: guokequan@hotmail.com

* Author to whom correspondence should be addressed; E-Mail: ikehara@hirakata.kmu.ac.jp;
Tel.: +81-72-804-2450; Fax: +81-72-804-2454.
External Editor: Katalin Prokai-Tatrai
Received: 6 September 2014; in revised form: 9 October 2014 / Accepted: 10 October 2014 /
Published: 23 October 2014

Abstract: Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder that
induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who
characterized the disease as causing memory loss and cognitive impairment. Pathologic
characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration.
Current therapies only target the relief of symptoms using various drugs, and do not cure the
disease. Recently, stem cell therapy has been shown to be a potential approach to various
diseases, including neurodegenerative disorders, and in this review, we focus on stem cell
therapies for AD.
Keywords: Alzheimer’s disease; stem cell therapy; oxidative stress; neurodegeneration

1. Introduction
Alzheimer’s disease (AD) is the most common form of dementia, which is one of the major causes
of disability and dependency among older people worldwide. AD manifests as an impaired ability to
comprehend or use words, poor coordination and gait, and impaired executive functions in the realms of
planning, ordering and making judgments. Generally, classification of AD includes familial and sporadic
AD. Familial AD presents mainly as the mutation of three genes: The amyloid precursor protein (APP),

2. Pathologic characteristics of AD are β-amyloid (Aβ) plaques. and activated complement proteins.Int. formed as abnormal hyperphosphorylation of tau protein. cytokines. Aβ oligomers are thought to be the most toxic due to their impairment of synaptic and neuronal functions. and generate ROS as a result of inefficient oxidative phosphorylation. Mol. An imbalance between oxidant and antioxidant agents could generate oxidative stress. astrocytes produce IL-6. indicating that Aβ deposits may also induce an anti-inflammatory effect. leading to neurodegeneration that is clinically manifested by memory and cognitive dysfunction [7]. but are active participants in neural information processing in the brain. APP is cleaved by α-. superoxide radical. and Aβ fibrils from pores in neurons have been shown to lead to calcium influx and neuronal death [3]. Sci. Aged microglia show a higher level of activation. It forms helical filaments and aggregates neurofibrillary tangles in the neuronal cytoplasm [8]. which is one of the microtubule-associated proteins [4]. neuronal dysfunction and death. Chronic neuroinflammation is one of the major factors in the pathophysiology of AD [10]. suggesting that anti-inflammation therapy may help prevent AD [10]. with apolipoprotein (ApoE) reportedly the most important [2]. separated from microtubules when it is phosphorylated. but APP generates Aβ through abnormal processing. resulting in a localized inflammatory state within the CNS. and that tau reduction can block Aβ. Recent research suggests that astrocytes are not simply passive support cells for neurons. Mitochondrial dysfunction occurs early and . Decreasing amyloid deposits and the use of antioxidant therapies have some ability to alleviate AD and.and γ-secretases.and excitotoxin-induced neuronal dysfunction in the AD mouse model [9]. Microglia activation and the release of associated inflammatory factors has been reported to contribute to chronic neurodegenerative disorders in AD [5]. cell therapy has been seen as a potential approach to its treatment. they undergo dramatic changes in morphology in response to injury [12. Oxygen metabolism generates free radicals such as hydroxylradical. microglia have been reported to play an important role in the immune defense system of the central nervous system (CNS). Microglia may release inflammatory cytokines. more recently. NFT consists of neurofibrillary protein aggregates. Tau is a neuronal microtubule-associated protein. Mitochondria contain many redox enzymes. IL-6 and TNFα. 15 19227 presenilin-1 (PS-1) and presenilin-2 [1]. Sporadic AD results from environmental factors and risk genes. chemokines. Oxidative stress is a sign of aging and an important pathogenic factor in AD. we focus on stem cell therapies for AD. Pathophysiology of AD The pathophysiology of AD includes loss of neurons and synapses in the cerebral cortex and parts of the subcortical areas [6]. In this review. such as in AD. and reactive nitrogen species. this disease being associated with an inflammatory response as a result of increasing numbers of activated microglia and astrocytes. J. inducing reactive oxygen species (ROS) [15]. TGF-β was detected around and within senile plaques in brains from Alzheimer patients. neurofibrillary tangles (NFT) and neurodegeneration. Aβ peptide is the main constituent of senile plaques. and anti-inflammatory drugs such as tenilsetam show beneficial effects in AD animal models. and while microglia remain in a resting state in the healthy adult brain. and release inflammatory cytokines such as IL-1. 2014. One report has indicated that Aβ may accelerate tau aggregation into NFT. and reactive oxygen [11]. and growth factors to remedy neuronal injury. β. Moreover. These pathological changes lead to synaptic loss.13]. Furthermore. generating a soluble peptide in normal people. which induces damage to macromolecules and disrupts the reduction/oxidation (redox) signaling [16]. which are associated with age-related cortical atrophy in humans [14].

Mol. And stem cell transplantation appears to increase acetylcholine levels to improve cognition and memory in the animal model [28]. and high levels of vitamin E have been shown to be related to a reduced risk of AD [26]. one report has shown that the transition metals such as Cu2+. Glutathione is an antioxidant in brain cells. although there are side effects in the treatment of AD [25]. and this can result in a therapeutic effect when these cells are transplanted into AD animal models. Vitamin E is another endogenous antioxidant that protects against lipid peroxidation. and tissue-derived stem cells. such as bone marrow (BM). a glutamate receptor associated channel blocker. Extracellular Cathepsin B is associated with amyloid plaques. Cathepsin B is a cysteine protease of the papain superfamily. Moreover. and colocalizes with Aβ in regulated secretory vesicles in chromaffin cells in AD brains [22]. AD therapeutic options also include acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine. which accumulates in parenchyma and blood vessels causes microglial migration and promotes inflammatory responses. 4.30]. at which time the escape latency was found to have significantly decreased when compared to sham controls. and degrades peptides and proteins that enter the endolysosomal system by endocytosis or phagocytosis [21]. and thus depleting Aβ should be a useful therapy for AD. suggesting that the activation of Cathepsin B could offer a therapeutic strategy for AD [23]. and that Aβ catalyses the reduction of Cu2+. Stem Cell Treatment for AD Stem cells include embryonic stem cells (ESCs). stem cells secrete neurotrophic factors to modulate neuroplasticity and neurogenesis [29. The Morris water maze test was performed 16 weeks after transplantation. Although . These results suggested that ESC-derived NPCs ameliorated memory impairment.Int.and adipose-derived stem cells. Sci. General Treatment for AD Deposits of Aβ are a pathological hallmark of AD. leading to the formation of proapoptotic lipid peroxidation products [18]. Aβ. J. Aβ also decreases ATP and increases ROS generation in mitochondria. Fe3+ and H2O2. Moreover. Moreover.20]. induced pluripotent stem cells (iPSCs). Zn2+ and Fe3+ are associated with Aβ aggregation and oxidative damage in the AD brain. totipotent cells that can differentiate into neuron progenitor cells (NPCs) in vitro. ESCs are self-renewing. Although vitamins C and E have been used in clinical applications to prevent AD. Neprilysin is another major extracellular Aβ degrading enzyme that clears Aβ from the brain. 15 19228 has a primary role in the pathogenesis of AD [17]. ESC-derived NPCs were transplanted into an Aβ-injured rat model and the escape latency was significantly increased compared to phosphate buffered saline (PBS)-treated controls 2 weeks after the Aβ injection. and the injection of human neprilysin decreased amyloid plaques in the transgenic mouse [24]. leading to cell apoptosis [19. Stem cell-derived neurons have the potential to integrate into the existing neural networks of the host brain [27]. Vitamin C is a water-soluble antioxidant that is necessary for the reactivation of vitamin E. 3. no clear beneficial effect has been demonstrated [2]. It reacts with ROS and oxidized products forming gluthathione disulphide. One report demonstrated that Cathepsin B reduces the relative abundance of Aβ through limited proteolysis. ESC-derived NPCs have been reported to be able to differentiate into astrocytic and neuron-like cells in vivo. 2014.

Human iPSCs were derived from skin cells by retroviral expression of octamer-binding transcription factor 4 (OCT4). and can differentiate into neural cells. adipose-derived stem cells (ADSCs) were isolated from the inguinal fat pads of rats. adipose-derived MSCs (AMSCs) improved Ach levels as well as cognitive and locomotor functions in aged mice. proto-oncogene proteins c myc (cMYC). These beneficial effects were associated with the activation of M2-like microglia [51. BMMSCs were able to remove Aβ plaques from the hippocampus and to reduce Aβ deposits through the activation of endogenous microglia in an induced AD mouse model [43. it has been shown that ESC-derived NPCs can treat neurodegenerative diseases [31]. accompanied with up-regulation of vascular endothelial growth factor expression and improvement of neural function. One report showed that induced iPSCs were generated from fibroblasts of familial ADs. The cognitive function was improved and Aβ deposition was reduced after transplantation. adipocytes. 15 19229 ESCs result in teratoma formation. and the umbilical cord [35]. promote Aβ clearance and increase neuronal survival in an Aβ-treated mouse model [45]. and pancreatic islets [36. Moreover.Int. Furthermore. IL-10. Moreover. and induced to differentiate into neurons or astrocyte-like cells in vitro. Human cord blood-derived stem cells have been shown to improve neuropathological and behavioral recovery from acute spinal cord trauma [50]. BMMSCs strongly inhibited the maturation and functioning of monocyte-derived DCs by interfering selectively with the generation of immature cells via the inhibitory mediator of MSC-derived PGE2. J. In contrast. MSCs have been shown to differentiate into osteoblasts. Sci. TGF-β. suggesting that ADSCs benefit neural differentiation and induce functional improvement in the rat [47]. suggesting that these neurons have a pharmacological response to γ-secretase inhibitors. human MSCs enhance autophagy. . BMMSCs were able to home in on the injured brain and increase the number of positive cells for choline acetyltransferase.44].49]. When human ADSCs were intravenously injected into an AD mouse models. Human umbilical cord-derived MSCs can be induced to differentiate into neuron-like cells. Mesenchymal stem cells (MSCs) are multi-potent progenitor cells that are mainly isolated from BM [33]. Mol. Thus these iPSCs may provide a potential strategy for the development of drugs against AD [32]. and PGE2 [38–40]. BMMSCs have been reported to have the ability to modify and influence almost all the cells of the innate and adaptive immune systems mediated by BMMSC-soluble factors. and these cells were transplanted into an amyloid-β precursor protein (AβPP) and PS1 (AβPP/PS1) transgenic AD mouse model. these cells could be found in the brain up to 12 days after their injection [48].52].42]. when transplanted into the brain. and kruppel-like factor 4 (KLF4).37]. One report suggested that. and modulated microglia activation [29. The transplantation of human MSCs has reduced infarct size and improved functional outcome. BMMSCs have also been shown to alter the natural killer (NK) cell phenotype. adipose tissue [34]. and that these iPSCs differentiated into neurons that may increase Aβ42 secretion. including IL-6. 2014. Aβ secretion from these differentiated neurons was affected by γ-secretase inhibitors. sex determining region Y-box 2 (SOX2). and autologous BMMSCs have been transfused to brain ischemic disease patients in clinical application [46]. and suppress the proliferation and cytokine secretion of NK cells [41. The transplantation of ADSCs allowed them to differentiate into neuron-like and astrocyte-like cells around the hematoma.

1. and pathologic phenotype. and this strain shows abnormal radioresistant stem cells [53]. life span. and Alzheimer’s disease [56–58]. HO-2 and HO-3. has been proven to be the best method for allogeneic BMT because hematopoietic recovery is rapid. IBM-BMT and Senescence-Accelerated Mouse Prone 8 (SAMP8) The senescence-accelerated mouse (SAM) was established via the selective inbreeding of the AKR/J strain of mice by Takeda et al. at Kyoto University. though this method failed in MRL/lpr mice because these mice are more radiosensitive after the onset of lupus nephritis [54]. One report has demonstrated that antisense oligonucleotides directed against PS-1 in old SAMP8 mice improved learning and memory deficits and reduced Aβ-mediated oxidative stress [66]. as was confirmed by immunoblot analysis. we have used IBM-BMT to successfully treat autoimmune diseases. and heavy metals. 15 19230 5. According to a graded score for senescence. IBM-BMT. and induced the excessive production of ROS and neurodegeneration in these two strains [59]. SAMP8 mice showed significant impairment in the passive avoidance response. These mice show age-related deficits in learning and memory and impaired immune response. since the stroma cells directly home to the bone cavity and the restoration of T cell functions is complete even in donor-recipient combinations across the MHC barriers [55]. Heme oxygenase (HO) is an enzyme that catalyzes the degradation of heme. Up to this point. Some Purkinje cells seemed to disappear with aging in the medial cerebellum and vermis of SAMP8. for the treatment of autoimmune diseases in MRL/lpr mice. 2014. There are three isoforms: HO-1. which was consistent with the finding in AD brains. We have reported that BMT plus bone grafts can prevent the recurrence of autoimmune diseases. oxidative stress has been shown to be associated with mitochondrial dysfunction. HO-2 is a constitutive isoform that is expressed under homeostatic conditions. as in IBM-BMT. Another report indicated that hydrocotyle sibthorpioides administration prevented declines in spatial learning and memory by the scavenging of free radicals. in responding to stress such as oxidative stress. presenting chronic over-expression in the AD brain [60]. decreasing the level of Aβ and ameliorating dysfunction in synaptic plasticity in SAMP8 mice [67]. Mol. . as shown by the enzyme-linked immuosorbent assay method. 4. Aβ-like deposition increased with aging. The SAMP8 was first reported to have age-related occurrence of deficits in learning and memory in 1986. there are nine SAM-prone (SAMP) strains including SAMP1-3 and SAMP6-11. However. Aβ has been shown to play a central role in the pathophysiology of AD through the induction of oxidative stress. Aβ levels in the hippocampi of SAMP8 increased with aging. We thus injected whole BM cells directly into the bone marrow cavity.Int. although no senile plaque-like structures were found. HO-1 was reported to respond to excessive amyloid provocation and mitochondrial insufficiency. Neuropathological studies showed that Aβ deposition was similar to that in AD in humans. Moreover. HO-1 is an inducible isoform. Moreover. Sci. and 5. which not only replaces hematopoietic stem cells but also MSCs. Moreover. Intra-Bone Marrow-Bone Marrow Transplantation (IBM-BMT) and AD Mouse Model The MRL-MpJ-lpr/lpr (MRL/lpr) mouse is a mouse model for autoimmune diseases. active avoidance tasks and spatial learning tasks when compared with age-matched SAMR1 [61]. 5. J. hypoxia. Thus the SAMP8 is shown to be an acceptable rodent model for AD [62–65]. and three SAM-resistant strains (SAMR) including SAMR1. osteoporosis. up-regulating the activity of antioxidant enzymes. we reported that BMMSCs can become trapped in the liver and lung when BM cells are injected intravenously.

accumulation of neuronal DNA damage. Escape latency of Senescence-Accelerated Mouse Prone 8 (SAMP8). although there was no difference in swim speed. and to reduce amyloid deposits via phagocytosis of Aβ and thereby prevent the progression of AD [68].73]. compared to age-matched SAMP8 [58]. 2014. and there were fewer segments and tips in the SAMP10 than in the SAMR1. shrinkage and loss of cortical neurons. Figure 1. Moreover. We used it for examining the effects of IBM-BMT on spatial learning and memory ability. reduced hippocampal cholinergic receptors. whole bone marrow cells from 8-week-old C57BL/6 mice were injected into the recipient mice. Analyses of the water maze tests showed the impairment of spatial memory in SAMP8 to have been ameliorated. The 4-month-old SAMP8 mice received fractionated irradiation twice a day (4. brain atrophy. increased sphingomyelinase. (a) Untreated SAMP8. and elevated oxidative-nitrative stress. The swim paths of SAMP8 treated with IBM-BMT were more directly toward the hidden platform than those of SAMP8. compared to age-matched SAMP8.Int. Three months after IBM-BMT. In contrast. the microglia showed a shorter combined projection length. SAMP10 also showed decreased catecholamine synthesis in the cerebral cortex. while TGF-β increased in the SAMP8 treated with IBM-BMT.5 Gy × 2. the levels of . the escape latency of SAMP8 treated with IBM-BMT was significantly shorter than that of age-matched SAMP8 (Figure 1). IBM-BMT and SAMP10 SAMP10 show age-related deficits in learning and memory as well as emotional disorders. 5. decreased neurotrophic factors. Sci.2. which is thought to be a sensitive assay for brain abnormalities. 15 19231 BM cells have been shown to increase the number of activated microglia. which is consistent with neuronal degeneration in the SAMP10. Western blot analysis to examine HO-1 expression showed a significant decrease in the ratio of HO-1 to actin in the SAMP 8 treated with IBM-BMT. However. especially in the hippocampus [69].and 7-month-old SAMR1. Proinflammatory cytokines are involved in the formation of neuritic plaques in Alzheimer’s disease (AD) [70. Our results suggested that IBM-BMT improved inflammation and oxidative stress in AD model mice. One day after the irradiation. with a 4 h interval). IL-1β and inducible nitric oxide synthase (iNOS) decreased. These mice were then tested by the Morris water maze test. there was no significant difference between the escape latency and the swim speed of 4. (b) SAMP8 treated with intra-bone marrow-bone marrow transplantation (IBM-BMT). J. and (c) SAM-resistant strains 1 (SAMR1). RT-PCR results showed that the expression of IL-6. related with the decline in learning and memory abilities with aging.71]. We used allogenic IBM-BMT to transfer normal BM stem cells in SAMP8. Mol. and SAMP 10 have thus also been extensively used in studies as AD model mice [72.

The immune system modulates CNS function and behavioral process. Our previous report suggested that bone marrow cells contain the precursors of functional TECs. peripheral immune cells (particularly T cells and macrophages). resulting in an increased risk of autoimmunity through the escape of potentially self-reactive T cells from the disrupted thymic microenvironment. Sirt1 is a class III histone deacetylase within the sirtuin family of related proteins that is uniquely dependent on nicotinamide adenine dinucleotide+ (NAD+) for catalysis. thereby correcting thymic function [81]. Mol. Normal aging is associated with anatomical and functional changes in both the thymus and bone marrow. Sci. IBM-BMT may thus prove beneficial in the experimental treatment of psychiatric and neurological diseases [82]. 15 19232 age-related pro-inflammatory cytokines such as IL-1β and IFN-γ showed greater increases in the SAMP10 than SAMR1 [74]. The aged thymus shows a disproportionate loss of thymic epithelial cells (TECs) and disrupted thymic architecture [77. neurons. . Under normal quiescent conditions. hippocampal long-term potentiation and neurogenesis. although there was no significant difference in the percentage of CD8 positive cells between 6-week. and that they can differentiate into TECs. memory and neural plasticity. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes). We first analyzed the lymphocyte populations in the peripheral blood by fluorescence-activated cell sorting (FACS). RT-PCR showed that downregulated KGF.78]. Sirt1 negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. the findings showed that the dysfunction on the TEC of 24-week-old SAMP10 was modulated by allogeneic bone marrow cells in this experiment. promoting memory consolidation. immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits. suggesting that the immune system was damaged in the SAMP10 [76]. Thus. J. Aire and Sirt1 was decreased on the TECs of 24-week-old SAMP10. Sirt1 has been implicated in processes as varied as metabolism. We investigated whether neurodegenerative diseases were associated with thymus dysfunction in SAMP10. differentiation. affecting the adaptive immunity. 2014. the percentage of CD4/TNFα T cells in the spleen of 24-week-old SAMP10 was significantly reduced compared to that of 6-week-old SAMP10. but the percentages of CD11b/Gr-1 double-positive cells were significantly higher in the 24-week-old SAMP10 than in the 6-week-old SAMP10. Aire and Sirt1 on the TEC of 24-week-old SAMP10 were improved after IBM-BMT. Our results showed that the thymus was significantly lighter and the percentage of CD4+CD8+ was lower in the 24-week-old SAMP10 than the 6-week-old SAMP10. suggesting that BMT might improve TEC function in SAMP10 [76]. Loss of Sirt1 function results in abnormally increased T cell activation and a breakdown of CD4+ T cell tolerance [80]. cancer. stress response and aging [79]. We will focus future studies on the affects of stem cell transplantation on the pathologic changes in brain. The immune system plays a central role in modulating learning. Moreover. The expression of keratinocyte growth factor (KGF).Int. Another report examined the finding that IBM-BMT facilitates the entry of transplanted BM cells into the brain parenchyma. and neural precursor cells [75]. Our results showed that the percentages of CD4 and B220-positive cells were significantly lower. The thymus is a source of T cells.and 24-week-old SAMP10.

. 2007. Cedazo-Minguez. 427318. Cell Longev. References 1. G. more advanced stem cell therapies hold the potential for the clinical treatment of this debilitating disease. 3. Cell Biol.. J. H. Munch. Sci. Haase. J. but stem cell therapy not only has the potential to generate new neurons and replace damaged neurons but also to modulate the immune system (Figure 2). Oxidative stress in Alzheimer’s disease: Why did antioxidant therapy fail? Oxid. 2. A. M.. A. R... 2014. and therapy.. Parker.M. Single-channel Ca2+ imaging implicates Aβ 1–42 amyloid pores in Alzheimer’s disease pathology. van Gool. 6984–6991. 15 19233 6. Figure 2.. C..J. Williams. Kequan Guo and Susumu Ikehara wrote the manuscript together. Mol. 40. Bate. With further clarification of the mechanisms by which AD progresses. Luth.J. Alzheimer’s disease: Genes. Persson. Rozemuller. I. 282. 2014. 515–524. Biol. Summary of Stem Cell Therapy for AD. Flach. T.O. 741–766. Conflicts of Interest The authors declare no conflict of interest. K. Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation. Arendt. Selkoe. 2014. Kuhla. J. T.. stem cell therapies may well prove to be both safe and effective treatments. B. 81.. Popescu. Physiol. For the most part. Author Contributions Ming Li. Hoozemans. 2011. 232–239. Med.J.. D. In time. W.. P..Int. 4. Rev.. Eikelenboom. Conclusions Aging is the greatest risk factor for the onset of AD. Smith. proteins. A. J. Neuroinflammation in Alzheimer’s disease and prion disease. 195.. C. Demuro. 2001. Chem.A. Veerhuis. Glia 2002. pharmacological interventions are aimed at relieving the symptoms of AD.. B. 5. J. Acknowledgments We would like to thank Hilary Eastwick-Field and Keiko Ando for their help in the preparation of the manuscript.

.. Radi..L. Chem. Cell Physiol.. 386. Gan.. G.. Yan. Neuronal receptors as targets for the action of amyloid-β protein (Aβ) in the brain. 22. C849–C868. H. Vlassara. J. Hook. Biochem.. C. 8. Jhamandas. Palop. 9. 13. Medzihradszky.L... 7. Perry. T. 2014. Mook-Jung. A... G. Wong. Y.. 21. J. 19234 Wenk... Inflammatory process in Alzheimer’s disease. R... Gerstein. Roberson.. Neurotherapeutics 2010. J. B. S. 10. Biol. Roberson. 7–10. Wang. E.. L...D. M. 23–34. J. Annu... A. Villeda-Hernandez. 59. oxidative stress and neurodegeneration. Neuropathologic changes in Alzheimer’s disease.. M. 2012. R. Sci. Emerging roles for cysteine proteases in human biology. 23. L. Durany. 14. J... Suppl. 12.Z. A. R.D. 16. E. M. G. X. Alzheimer’s disease—Synergistic effects of glucose deficit. W. J. and biological reducing agents to neurotoxic H2O2. M.H. K. D. Chem. J. G. White. Zweier.. 14. J. Meraz-Rios. 15 6. 931–940.. 2005. Rev. 160–170. P. A.A. Scearce-Levie. Lane. Khatoon. Int. Res. 51.F. D.. 366–377. 750–754. 2011. 17. Science 2007. Karunaweera. Biol. 20.C.R. 169–180. Franco-Bocanegra.S. Son.. 316. C. Loane. 1998.. P. PLoS One 2012. E. Roher. Neural Transm. S.. I. Vilhardt. e34929. Association between cytokines and cerebral MRI changes in the aging brain.. Mucke.L. Rothermundt.R. J. Role of microglia in neurotrauma. Yu. oxidative stress and advanced glycation endproducts.. Inestrosa... V. Pei. X. N. Mol. A. Integr. T. 105. Li. 322.. L. Med. cholesterol. Geriatr. Microglia: Phagocyte and glia cell. Biomed. S. N.N.. Metalloenzyme-like activity of Alzheimer’s disease β-amyloid. P... Sonego. N. J. Radical-free biology of oxidative stress.. Mol. Byun.. Cherny. Berger. Schinzel.E.A.H. Tanzi. Millington.N... Y.. Sun. Campos-Pena. Munch.. Huang. J. 2005. Alonso.J.. Inhibition of cathepsin B reduces β-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: Evidence for cathepsin B as a candidate β-secretase of Alzheimer’s disease.. 19. 703–714. D. J. Zhou. Psychiatry Neurol...M. 2014. 59. 51... G.. 2008.. Expert Rev. C. C.. C.. 295. K. A. 11. 254–262. . I. Moir. D. Munch.J.. G. J. Patel. 2014.. Iqbal. Neural Transm. Neveu.. J. Mucke. Wang.R. Med. G. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. M. Cardaioli. G. Psychiatry 2003. 37. S. Chen. S.P.. Shi. Antiamyloidogenic and neuroprotective functions of cathepsin B: Implications for Alzheimer’s disease.D. Loske. Velayutham. 277. Physiol. Cheng. E. G. Chapman. Hemann. Grundke-Iqbal. Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles.C. Free Radic. Greenbaum. Jones. 18. et al. Cu-dependent catalytic conversion of dopamine. J. 2012. Formichi.. A. H. Gyengesi. R.J.. H. T. Hong.J.P. F.H. V..Int. 7. Han.. Reisine. Clin. Toneff. J. 2013. Masters. Sci. Cappai.J.. Roesler. Bogyo. Esposito. J. Riese. Yu. Mueller-Steiner.J. 2009. J. 439–461.. K. 15. I. Riederer. Am. G. Campbell.. 40302–40308. B. Byrnes.. M. Choi.X. Neurosci. 1997. I.. Int.. 64. Mitochondria.T. Gallus. J. Neuron 2006. 309129. K.A... Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death. E. Toral-Rios. Front.. 22. Arai. D..E. 1998. C. Federico.Q.... Baune. L. e2. Chronic neuroinflammation in Alzheimer’s disease: New perspectives on animal models and promising candidate drugs. 7. Hook. Cell Biol. F. 7. J. Ponath. A. 17–21. H. Physiol.L... Smith. Aldrich-Wright. Gong.Y. R. Cha. da Pozzo. Neurol.A. Removal of H2O2 and generation of superoxide radical: Role of cytochrome c and NADH. Wu.. 53. K. Biol. 63–88.. 2002. Opazo.. R. Rangel. H...

J. 29..A. H. 2001.. Minguell. Xu. Zuk. 2008.. Mol. Popescu.. Y. Nat. Fan. L. 33.. Park.. Kim.S. Katz. 75. The International Society for Cellular Therapy position statement.Q. D. High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age. I.C. 98.. L. K.... Mevorach. Bae.. Ayala. Nicolescu. Zhou. P.H...A. Mecocci. D.. M. T..J. Blood 2001. G.. Mesenchymal progenitor cells in human umbilical cord blood. Fisk. Burkhardt. 109. Keating. Enciu. Neurosci. 2000. Huang. Yang. Xia. 11... D. Deans.M. Aging 2013. Diabetes 2004.K. Marini. S. Weick. J.. 30. A.. 1029–1037. 15 19235 24.. Biotechnol. Haematol. Neurosci. Ma. Aslan.J. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood. D. Krencik.. J.G.. H.. Z. 28. Lee. F. J.. Kim. 23. 660–670.. D. Res. Mangialasche.. E. 32.A. liver. Krause.. 2011...U. Erices. Yamanaka.. Massoud. Yang..H... S.. 2639–2646. B. BMC Neurol. M. L.P. 2214–2219. S. L. J. S. Benhaim... 2003. B.P. Hersh. P. M. Kindy. Zhang. G... R.M. 315–317. 2013.. Verma. D. J. Litherland... 31.. N.. 25. Embryonic stem cell-derived neural precursor cells improve memory dysfunction in Aβ(1–40) injured rats. Palmer. P. 2011. Neurosci. Pharmacological treatment of Alzheimer disease. Tang. 440–447. I. 105. Genet. Manole. .. Galun. et al. C. S. 62. Winblad. N. Roberts. J. S. 31.. Lee. I. H. 2396–2402. 20. 1992–1996. Tissue Eng. Choi. Kivipelto. Zhou. Yagi. Choi. S.. Gage. Cytotherapy 2006. J. Conget.....K. 2014. Multilineage cells from human adipose tissue: Implications for cell-based therapies.. Dominici. Liu. Zhang. 211–228. D. Minimal criteria for defining multipotent mesenchymal stromal cells. 34.C.. D. Mukherjee. Sci..M. Rachmilewitz.. Beyth. Kyung. Prockop. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Rancourt..W.. J. Li... Bae. F. R. M. 26. E. C...A. Choi. Kyung. D. Ito.. D. M. Y..B. Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase. P.. Z. Bellantuono. 27. G.A. 36. E. Yang. E.. Muresanu.. Blood 2005. H. Rockenstein. P. Lorenz. Nihei.. 8. le Blanc. A.. X.H. Alzheimers Dis. Slaper-Cortenbach.. M. Akamatsu.M. Mizuno.I. Lee.H. K. Okada.. Mueller. G. M.. B.K. S. Y.. Suzuki...W.R. Br.. Bennett. Rizzuto. F. Res. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. 56.. 34..Z. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Hedrick. E.K.H. Can. Tang.. Kim.. Yang..J. Mol. 7... 579–588.. S. X. J. Zhu. I. D. Z.C. W. D. Neuroregeneration in neurodegenerative disorders. J.. Borovsky. K. D. R. Yang.. Hum. Cao. L. Futrell. A. G.. Horwitz.M. Kumar... 38. 2013. C. F. 53. Liu.H. 35. 91. and bone marrow. T. Li. Fratiglioni.. I. Kim. 4530–4539. 37. Y. 20. H. Y. Liebergall.Int. et al. Leger. J. J. Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice.. G. D.. Park. L. Neurobiol. D. 86–96. Atkinson. Marr. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. 2010..Q..H. M.R. H. Gazit.F. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Psychiatry 2011... L. Okano. J.O. E... A. M. Popescu. 235–242. Masliah. A. Yoshizaki... Yang. Campagnoli. 1721–1732.

Ha. Bone marrow-derived mesenchymal stem cells reduce brain amyloid-β deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model.. 2013. J. 1790–1807... B. 2007... H. Hendricks. A. 353–363. Y.. S. Ni... C. E... Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models.M... doi:10. 412–421. S. X. Lee. C. Yang.K... 105.X. B. Tan. 19. 135.Y.. Mori.. et al.. Dazzi. Wang. Brain 2012.. Hu.. Baxevanis. H. Sci. Ehrhart. Gasis..A. Zhao. T. C.. 18.... P. P. Autophagy 2014. In vivo imaging of human adipose-derived stem cells in Alzheimer’s disease animal model. Hartung. F.. 44. Biomed. Wang.. Atta. 47. W. I..S. F. Barry. Xie. 2014. Huang.. Human mesenchymal stem cells modulate allogeneic immune cell responses.Q.. Salem. 136–141.M. Y. Sanberg. P. Bae. G. S. 22. Yan. Estrada. 2013. 43. Zhang.J. Soeiro.J. Schmitz. Exp. Ishiai.. Pittenger. 4.A. J. Cell Biol. Sotiropoulou. Transplantation of adipose-derived stem cells is associated with neural differentiation and functional improvement in a rat model of intracerebral hemorrhage. 134. Z. 2014.. 83. Zeng. Stem Cells Dev. Chen. B. 1815–1822. et al. 149. Zhang. 2013. J.. Potential of bone marrow mesenchymal stem cells in management of Alzheimer’s disease in female rats. Liu.. 52. 450. Niitsu.. Song. Kocsis. S. J. M. 45. Murphy. J.. Zhu. G.. M. Clin.. Ryan. Significant clinical.. Q.. Blood 2005.. J. 2009.. Lombardi. S.N.. Onodera... R. T.Int. T.. P.. Ahmed. D. O.D.. J.M.M. 24. 46. J. H. Neurosci.. M.A. CNS Neurosci.K... 2014. N. S. 15 19236 39.H. Aglan..10331. Gong.. Wei. Kim. Darlington.M.. C.G. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Y.. Shin. Kuzmin-Nichols. Brain 2011.J.. J. Jin. Waxman. Liu. Transplantation 2007. Cell Transplant.1002/cbin.. M.X. Suh. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice. Ther. S. S.. J. Intracerebral transplantation of adipose-derived mesenchymal stem cells alternatively activates microglia and ameliorates neuropathological deficits in Alzheimer’s disease mice. Ao. Lett. H. 76. S113–S126. Hou. Interactions between human mesenchymal stem cells and natural killer cells.R. S. Honmou. J.. neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Trapp. 40.. 051206.. Park.. H.D. H. 847–854. Chang. Papamichail.. J. Deng.M. F. Y.P. Matsunaga. 32–44. Y. 50. but promotes the immunosuppressive capacity of adult human mesenchymal stem cells...A.H.. N.. 42.. J. Opt... Wernet. Interferon-γ does not break. 22. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. S. P. K.. Y. Ha.. 2012.D.. Kruse. 48.. Perez.. Houkin. Stem Cell Res. Bi. Tang. Schira. Lee. H.P. Kogler. H.. J. Yang.N. X. T. V. H. Lam. A. 10.. 51.. Z. Ghazy. Sanberg.H. Fazekasova. Zhao. Ahn. H. Gritzapis. Bae. K. Zhou. Stem Cells 2006. Aggarwal. Mahon.. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-β deposition in an AβPP/PS1 transgenic mouse model..W. Joo.H. Ramasamy.. F.. Giunta. 431–446. 41. Immunol. Oh. Chong. K. R. . 74–85. Mol. B. Int. L. Kim. Gong.D. Y. 49. H. H. Y. J.S.A.. Y. 71–76.G. Ma. H. Ther. H.H.

β/A4 proteinlike immunoreactive granular structures in the brain of senescence-accelerated mouse. Franko. H. J. Disord. V.. 821–830. Shimada. B52–B59. Farr. S. 66. Free Radic. 1993. USA 1989. R. S.. Toki.. H. Ikehara. 97.B. Neurosci.L. Cini. S. K. Ogawa. Kushida. T. . 63. Farr. S. et al.. Good. Ueno.M. Adachi. 47. 21. M. 58. Ueda... Inaba.. Proc. 2000. Iwai. M. S..A.. Morley. Guo. Sci. Blood 2001. N... Ikehara. Ikehara. Iida. A. N. S. 679–687... Acad.. 34. Ichioka.. H. 1994. Y. S. M.. Takei. Sultana. E. H.. 1992. A. R. Furukawa. Perluigi. Amelioration of cognitive ability in senescence-accelerated mouse prone 8 (SAMP8) by intra-bone marrow-bone marrow transplantation. Sci.. J.. Chiba.... 12.. Morley..E. N.B. T. Kawamura.. K. Heme oxygenase-1: Role in brain aging and neurodegeneration.. Banks.E. Ueda. The senescence-accelerated mouse (SAM): A higher oxidative stress and age-dependent degenerative diseases model. Oka.. A. T. Ikehara. Kamlesh. Y. et al. Cenini. 2009. J.. Kushida. Schipper. J. R. H.. T.. Treatment of senile osteoporosis in SAMP6 mice by intra-bone marrow injection of allogeneic bone marrow cells. H.. Sjobeck. Abraham. Ishida. Behav. Kiyota. Oe.... Hisha. M. K.. J. 3119–3127.. 54. Flood. M... Inaba. J. J. 3306–3310.. 2009. Nakamura. S. N. 142. Complete prevention of recurrence of autoimmune diseases in MRL/MP-Ipr/Ipr mice by transplantation of bone marrow plus bones (stromal cells) from the same donor. J. Am. Li.. V. Ikehara. Lett. Taira. Baba... 2009. Ishikawa. S. M. 56. Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Hayakawa. Natl. Pathol..A. Iida. N. Res. 399–406..... Gerontol. Y. Shimada. 32. Cai. Yasumizu. M. X.. Takeda. Y.. Sugiura.. T. Autoimmun. 1–14.. M. A. 61. N.. M. Nakamura. J. Yamazaki. 216–222..... S. Hisha.G... 57. 2013. 3292–3299.. Cogn. R. 1887–1897.. Nagata. Kimura. Ogawa.F.. J. Esumi. Hisha. 1769–1775. Immunol. M. Biol. 38. Forster. Geriatr. 211–218. Allogeneic intra-bone marrow transplantation prevents rheumatoid arthritis in SKG/Jcl mice. J. M. Mizokami. Inaba. N. Takeda. K. 1986. C.. K. 465. M.. R.. 55.G. S.. Peptides 2000. T. Physiol. Sakura. T. Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation. 399–405. Matsuo. Intra-bone marrow injection of allogeneic bone marrow cells: A powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice.. 60. Okamoto. G.. Gershwin. 36–40.. Takada.F... Sekita. 24. W.A.... Englund. Abraham. Wang. Miyamoto. S.. K. Akiguchi. 86. Nagawa. Alzheimer’s disease and the cerebellum: A morphologic study on neuronal and glial changes. Sugiura. N. N. 152. J. Early onset of age-related impairment of aversive and appetitive learning in the SAMP8 mouse. Y. K. Gerontol. Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. S. Neurochem. Inaba. Yoshikawa.... Iida. 15 19237 53.. Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment: A proteomics study. M. Ichioka. Exp. J. Nagaoka. Mol. Klein. T. M. Med. Hosokawa.Int. 65. Takemura. 35.. et al. Umeda. A. Fiorini. Flood. Allan butterfield.A. H. T.. Y. K. 62.E.. Inaba.. 2014. S. M. Age-related changes in learning and memory in the senescence-accelerated mouse (SAM).. 2001. M. Kumagai. H. 59.. N. 65. 64.. Stem Cells 2006. M. Ishii. Niehoff.. I. M.. Izui. Dement.. Kumar.

K. 25. Lee. B. Investig.K. Hasegawa-Ishii. Simard. Shimada. .... Mech. M. neural plasticity and neurogenesis. Iguchi.. 78. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. M. 68. A. G... Skelton.. 223–230. Bilateral knife cuts to the perforant path disrupt spatial learning in the Morris water maze. A. R. T. Gui. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Wu.F. Clin. N. 77. J... turnover. Inaba. 1553–1561. H.. 2014. Ikehara.L. Hosokawa. S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease.. Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus. 2. 2014..R. N. Takei. J.M. S. 87. 414–435. Switzerland. Jonas. Shimada. Y. Fitoterapia 2013. T.. et al. J. Hosokawa. S. Strauss. 2007... T. Brain Behav. Kawamura.Int. J. L. Y. Matsushita. S. Yirmiya... Rivest. Furukawa. Pathobiology of the senescence-accelerated mouse (SAM).G.org/licenses/by/4.. C.. Chen. 2011.. X.. Neuron 2006.. Lew.C. Volk. Senescence-accelerated mice (SAMs) as a model for brain aging and immunosenescence. Hosokawa. M. 117–127. Basel. Takaki. R. Zhang. Li. McNamara. 81. Immun. Braley-Mullen.. Lin. 79.. L. 123. 2011.. licensee MDPI. 1201–1211. T. H. J. Higuchi. S.. 80. J.. Milton. Abraham. Ikehara. X.M. 70.. Liston. Aging Dis. Lab. M. H. Huang. A. S. Wei. 1997. Zhu. T. P. R. X. Soulet. 75.... A. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons. M. S. Detection of interleukin-6 and α 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Gray... Neuropathology 2011. Aging 2011. M. D. Cui. M.. 29. 23. 181–213. Hosaka. Shi. Hosokawa..F. A higher oxidative status accelerates senescence and aggravates age-dependent disorders in SAMP strains of mice. Chen. K.. 2002... 76. A. 19. Takemura. S. J. Brain Behav. M. 489–502.. 66. N... Shi... McBurney. S. 31. Miyake. 74. Ikehara. 1019–1029. Ageing Dev. Kawamura. M. Presence of donor-derived thymic epithelial cells in B6→MRL/lpr mice after allogeneic intra-bone marrow-bone marrow transplantation (IBM-BMT). 3048–3058. A.P. S.W. 2013. Immun... S. 15 19238 67. V. I. Huang. Boyd. Shimada. Fraga... Cheng. W. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Immune modulation of learning.M. Su.. Sci.. © 2014 by the authors. Berger. Shannon. Gowing. M. A.... D.W. 1992. L. 32. Umegaki. K. S.0/). D. Calvanese. Blood 2006. 82... J. Dohkan.. Gerontol. 71. Divekar. T. M.. Inaba. M. Chiba. M. K. Sirt1 brings stemness closer to cancer and aging. 49. Exp. Tang. 162–167. 20–28.. Li. Takei. 2. 3. Investig. 69–77.. Autoimmun. 119. Takeda.. Hasegawa-Ishii. A. memory. 2009. 72. Improved expression of Sirt1 on thymic epithelial cells of SAMP10 after intra bone marrow-bone marrow transplantation. U. Goodnow. N... Gao. Hippocampus 1992. Mol. 82–97.. A. 73.. Developmental kinetics. U. R. Julien. Zaghouani. Barnes.. Nishida. Goshen. 3777–3785.. Zhuo.. 2008.H. 108. Hasegawa-Ishii. R. 31.. 408–415. and stimulatory capacity of thymic epithelial cells. M. 73–80. Morphological impairments in microglia precede age-related neuronal degeneration in senescence-accelerated mice. Ueno. Cell Transplant. A. B. Yoshikawa.. Int. N. 69... Bauer.. Kurozumi. Immunol.. Zhang. Chiba. Q. Ganter.. R. S.W.. M. Seach.