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REVIEW ARTICLE

published: 13 August 2013


INTEGRATIVE NEUROSCIENCE doi: 10.3389/fnint.2013.00059

Inflammatory process in Alzheimers Disease


Marco A. Meraz-Ros 1 , Danira Toral-Rios 2 , Diana Franco-Bocanegra 3 , Juana Villeda-Hernndez 4 and
Victoria Campos-Pea 5*
1
Departamento de Biomedicina Molecular, Centro de Investigacin y de Estudios Avanzados, Mexico City, Mexico
2
Departamento de Fisiologa Biofsica y Neurociencias, Centro de Investigacin y de Estudios Avanzados, Mexico City, Mexico
3
Posgrado en Ciencias Biolgicas, Universidad Nacional Autnoma de Mxico, Mexico City, Mexico
4
Departamento de Neuropatologa Experimental, Instituto Nacional de Neurologa y Neurociruga, Mexico City, Mexico
5
Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurologa y Neurociruga Manuel Velasco Surez, Mexico City, Mexico

Edited by: Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of
Beatriz Gomez-Gonzalez, dementia. Histopathologically is characterized by the presence of two major hallmarks,
Universidad Autonoma
Metropolitana, Unidad Iztapalapa,
the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs)
Mexico surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments
Reviewed by: of truncated tau protein that is abnormally hyperphosphorylated. The main component
Benjamn Florn, Centro de in the NP is the amyloid- peptide (A), a small fragment of 4042 amino acids with a
Investigacin y de Estudios molecular weight of 4 kD. It has been proposed that the amyloid aggregates and microglia
Avanzados del IPN, Mexico
Clorinda Arias, Universidad Nacional
activation are able to favor the neurodegenerative process observed in AD patients.
Autnoma de Mxico, Mexico However, the role of inflammation in AD is controversial, because in early stages the
Abbas Mirshafiey, Tehran University inflammation could have a beneficial role in the pathology, since it has been thought that
of Medical Sciences, Iran the microglia and astrocytes activated could be involved in A clearance. Nevertheless the
*Correspondence: chronic activation of the microglia has been related with an increase of A and possibly
Victoria Campos-Pea, Laboratorio
Experimental de Enfermedades
with tau phosphorylation. Studies in AD brains have shown an upregulation of complement
Neurodegenerativas, Instituto molecules, pro-inflammatory cytokines, acute phase reactants and other inflammatory
Nacional de Neurologa y mediators that could contribute with the neurodegenerative process. Clinical trials and
Neurociruga Manuel Velasco animal models with non-steroidal anti-inflammatory drugs (NSAIDs) indicate that these
Surez, Insurgentes Sur 3877, ZIP
14269, Mexico City, Mexico
drugs may decrease the risk of developing AD and apparently reduce A deposition.
e-mail: neurovcp@ymail.com Finally, further studies are needed to determine whether treatment with anti-inflammatory
Present address: strategies, may decrease the neurodegenerative process that affects these patients.
Marco A. Meraz-Ros,
Keywords: Alzheimer disease, amyloid-, neurodegeneration, microglia, astrocyte, neuroinflammation,
Departamento de Biomedicina
pro-inflammatory cytokine, anti-inflammatory strategies
Molecular, Centro de Investigacin y
de Estudios Avanzados, Av. Instituto
Politcnico Nacional 2508, ZIP
07360, Mexico City, Mexico

INTRODUCTION In addition to this multi-genic complexity in AD, now we


Alzheimers disease (AD) is the most common cause of dementia know that A promotes an inflammatory response mediated
in elderly adults. AD is clinically characterized by progressive loss by microglia and astrocytes, thus activating signaling pathways
of memory and other cognitive functions. Histopathologically that could lead to neurodegeneration. It is currently unknown
is recognized by the presence of neuritic plaques (NPs) and whether brain inflammation in AD patients is the cause of the
neurofibrillary tangles (NFTs). The origin causes of AD can disease or a secondary phenomenon. Although it was previ-
be classified as familial or sporadic. The incidence of famil- ously thought that the central nervous system (CNS) was an
ial cases is low (510%) and is related to the presence of immune-privileged site, now is well known that certain fea-
mutations in three different genes: presenilin-1 (PS1), presenilin- tures of inflammatory processes occur normally in response to
2 (PS2), and amyloid- precursor protein (APP-) (Chartier- an injury, infection or disease. The resident CNS cells generate
Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991; inflammatory mediators, such as pro-inflammatory cytokines,
Levy-Lahad et al., 1995; Duff et al., 1996; Sisodia et al., 1999). prostaglandins (PGs), free radicals, complement factors, and
Sporadic AD represents 9095% of total cases, and although its simultaneously induce the production of adhesion molecules and
etiology is multi-factorial, age is the main risk factor. Although chemokines, which could recruit peripheral immune cells. This
there are different genetic and environmental causes, all patients review describes the cellular and molecular mediators involved in
have a similar clinical behavior and develop identical brain the inflammatory process associated with AD and several possible
lesions: NFTs consisting of Tau () protein and NPs consist- therapeutic approaches describe recently.
ing of amyloid- (A) peptides. These alterations are the final
result of post-translational modifications and involve different NPs AND A IN THE NEURO-INFLAMMATORY PROCESS
genes and render AD as a complex multigenic neurodegenerative NPs, are extracellular deposits structures that contain a highly
disorder. insoluble fibrillar A core formed by fragments of 3942 amino

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

acids surrounded by microglia, reactive astrocytes, and dystrophic in AD patients (Glenner et al., 1984); this hypothesis was sup-
neurites produced from degenerating neuronal processes (Iversen ported by several studies (Rozemuller et al., 1986; Dickson et al.,
et al., 1995). A normally originates from APP- (Kang et al., 1988).
1987) through the sequential action of beta secretase and the Normally, microglia exists in an inactive state; morpholog-
multi-protein gamma-secretase complex. ically, these cells have a small soma with branching processes.
A accumulation in the brain, in one of the main patholog- When activated by pathogens or injury, these cells suffer visible
ical processes of AD patients. The formation of these deposits morphological changes, including decreased branching and soma
initiates a series of cellular events which are able to elicit an growth, the acquisition of an amoeboid form and display a wide
immune response where resident cells such as microglia and variety of specific cellular surface markers (Town et al., 2005). NPs
astrocytes could participate. A accumulation in parenchyma and in AD patients brain activate the inflammatory response medi-
blood vessels causes microglial migration and promotes acute ated by microglia and cause pro-inflammatory cytokine secretion,
and chronic inflammatory responses against the aggregates, thus which may directly cause neuronal injury.
inducing the production of nitric oxide (NO), reactive oxygen Microglia in vitro cell cultures are able to phagocyte the amy-
species (ROS), pro-inflammatory cytokines (TNF, IL-1 and IL- loid peptide. However, ultrastructural analysis of tissues from
6), and PGs (PGE2), which eventually could promote neuronal AD patients demonstrated that there is no presence of amy-
death (Figure 1) (Akiyama et al., 2000; Kitazawa et al., 2004). loid fibrils in the lysosomal compartments of local microglia
cells (Frackowiak et al., 1992). Whereas microglia has the abil-
CELLULAR MEDIATORS ity to phagocyte A in vitro, its phagocytosis capacity is limited.
MICROGLIA An important observed feature was the abnormal presence of
Microglia are resident brain cells, derived from monocyte precur- macrophages infiltrating from the periphery, which showed amy-
sors cells during embryogenesis, and are able to provide the initial loid fibers in their lysosomal compartments (Wisniewski et al.,
response against any injury that occurs in the CNS. Although 1991; Akiyama et al., 1996). Currently, we know that there are
these cell were observed by Nissl over 100 years ago, their defini- two types of phagocytic cells within the CNS that are able to
tive identification and characterization was performed by Mrak initiate the innate immune response: microglia and peripheral
(2012). Activated microglial association around NPs suggested macrophages (Rezai-Zadeh et al., 2009; Gate et al., 2010). These
that microglia participate in the accumulation of the A observed macrophages are recruited into the CNS by specific cytokines and

FIGURE 1 | Inflammation in Alzheimers disease. The A peptide produced These inflammatory factors directly acting on the neurons and also stimulate
by APP processing, form aggregates that activate microglia through TLRs and the astrocytes, which amplify the pro-inflammatory signals, inducing a
RAGE receptors. These receptors in turn, activate NF-B and AP-1 neurotoxic effects. The inflammatory mediators generate by resident CNS
transcription factors, which induce the reactive oxygen species (ROS) cells, induce the production of adhesion molecules and chemokines, which
production and the expression of inflammatory cytokines (IL-1, IL-6, TNF). recruit peripheral immune cells.

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

chemokines, which are released during microglial and astrocytic causing local inflammation that eventually could intensifies neu-
activation and are able to cross the blood-brain barrier. ronal death.
Similarly to macrophages, microglia recognizes pathogens Overall, the inflammatory process in AD patients is shown
through pattern recognition receptors (PRRs), which include by changes in microglial morphology and astrogliosis, which is
specific toll-like receptors (TLRs), nucleotide-oligomerization manifested by an increase in number, size and motility of astro-
binding domain (NOD) proteins, and C-type lectin recep- cytes. Astrocyte activation is present in many neurodegenerative
tors. These receptors interact with pathogen-associated molecu- conditions, expressing high levels of glial fibrillary acidic pro-
lar patterns (PAMPs) or damage-associated molecular patterns tein (GFAP), vimentin, and nestin. Unfortunately, these changes
(DAMPs) to initiate the cellular defense mechanisms (Sterka and cause a disruption of normal activities in astrocytes, which
Marriott, 2006; Rubartelli and Lotze, 2007). Thus, the forma- are essential for normal neuronal function. Maintenance of glu-
tion and release of ROS, pro-inflammatory cytokines (IL-1, tamate concentration in the extracellular space is among the
IL-6, TNF-, and IFN-) (Lue et al., 2001), chemokines (MIP1, normal physiological functions; altering homeostasis causes a
MIP1, RANTES, and MCP1), and growth factors such as local neuron depolarization, which leads to citotoxic damage.
macrophage colony-stimulating factor (MCSF) and complement Thus, although astrocytic activation has a protective role in brain,
factors (C1q, C3, C4, and C9) (Walker et al., 1995) begin. In intense activation exacerbates neuronal damage and accelerates
addition to the before mentioned molecules, microglia is also disease progression.
able to express receptors for advanced glycosilation end products Similarly to microglia, astrocytes quickly respond to injury;
(RAGE), Fc receptors, CD40, FP receptors, and various scavenger- these cells are located near the fibrilar A deposits, which are
type receptors (El Khoury et al., 1998; Tan et al., 1999; Walker responsible for the astroglial activation observed in AD patients.
and Lue, 2005; Okun et al., 2010). Although microglia has the Injection of A oligomeric forms into the retrosplenial cor-
capacity to respond to various stimuli, the presence of A is tex of rats caused a significant astrocyte activation, as shown
particularly important. A induces a high accumulation of sur- by transcription factor NF-B activation and the presence of
face molecules of type I and II major histocompatibility complex inflammatory mediators such as tumor necrosis factor (TNF-),
(MHC) (McGeer et al., 1988). interleukin 1 (IL-1), and cyclooxygenase-2 (COX-2)(Carrero
Microglial cells primarily have an immunomodulatory role et al., 2012). The activated astrocytes express on their cell surface,
and express a large variety of immune response-related antigens receptors that bind the A peptides such as RAGE, receptor-like
and molecules; however, the specific role of microglia within the density lipoproteins, proteoglycans and various scavenger recep-
CNS remains controversial. Microglial activation is not a sim- tors (Wyss-Coray et al., 2003; Medeiros and Laferla, 2013). Thus,
ple and unique phenomenon; instead, activation is a continuous activated astrocytes are able to cause neurodegeneration and
series of events in which microglia awakens innate and adaptive express inflammation-associated factors, such as S100, conse-
phagocytic immune responses and consistently display activa- quently inducing neurite outgrowth. S100 expression correlates
tion through antigens on the cellular surface (Town et al., 2005). with the number of dystrophic neurites in AD patients (Mrak
Under this principle, microglia displays a variable response, in et al., 1996).
which a mixture of the classical activation pathway and exacer- In astrocytes, NF-B significantly controls chemokine and
bated increase of alternative activation can be observed in AD adhesion molecules secretion, favors peripheral lymphocyte infil-
patients, which could leads to irreparable damage that result in tration and increases inflammatory response (Moynagh, 2005);
persistent neurodegeneration. this process becomes a self-regulating mechanism, which leads to
neurodegeneration.
ASTROCYTES
Astrocytes are the most abundant glial cells present in the CNS OLIGODENDROCYTES
and have important functions in brain organization and main- Although oligodendroglia is important to maintain neuron mor-
tenance (Sofroniew and Vinters, 2010). These cells interact with phology and function, little is known about how they are affected
neurons and are involved in neurotransmitter secretion and recy- by A deposits However, there are studies that indicate changes
cling, ion homeostasis, energy metabolism regulation, synaptic in white matter and abnormalities in myelin in AD patients
remodeling and modulation of oxidative stress, information pro- (Kobayashi et al., 2002; Roth et al., 2005). Specifically, aberra-
cessing, and signal transmission (Halassa and Haydon, 2010; tions have been reported in the white matter of asymptomatic
Henneberger et al., 2010). familial AD patients, particularly in patients with mutations in
In early stages of AD, activated astrocytes are located in two PS1 (Ringman et al., 2007). The presence of A in oligoden-
regions: the molecular layer of the cerebral cortex and near the drocyte cultures caused cell death. Although cell death can be
amyloid deposits below the pyramidal cell layer. The mecha- prevented by the presence of anti-inflammatory agents, morpho-
nisms leading to the activation of these cells in response to the logical alterations of the cells persist, suggesting that the damage
pathological changes produced by AD are not obvious, but it has cannot be completely reversed (Roth et al., 2005). Subsequently,
been demonstrated that the presence of amyloid activates astro- oligodendrocyte differentiation and function is affected by the
cytes. Activated astrocytes can phagocytose and degrade amyloid, simultaneous presence of mutations in PS1 (hPS1M146V ) and
which suggests that they importantly contribute to the removal A accumulation, as demonstrated in a mouse model. These
of accumulated A in parenchyma. Astrocytes and microglia are abnormalities can lead to the development of abnormal pat-
activated through TLRs and RAGE-dependent pathways, thus terns of myelin basic protein (MBP) (Desai et al., 2011),

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

which completely alters oligodendrocyte homeostasis. Finally, the response, the complement system is involved in T-cell response
loss of trophic support provided by these cells might lead to regulation and T-helper lymphocyte differentiation (Pekkarinen
increased neuronal vulnerability and inflammation, thus favoring et al., 2011).
neurodegeneration. In neurodegenerative diseases, there is a deregulation of the
classical complement pathway. Studies in AD patient brains have
MOLECULAR MEDIATORS OF INFLAMMATION IN AD revealed an increase in the immunoreactivity of C1q, C3b, C4d,
The A deposition activates the acute immune response of C5b-9, and MAC surrounding senile plaques (McGeer et al.,
microglial cells and astrocytes. At the same time, amyloid 1989; Rogers et al., 1992) and microglia surrounding the fibrillar
plaques are responsible for the production and the activation aggregates of A in the microvasculature (Fan et al., 2007). The
of inflammation-related proteins such as complement factors, co-existence of these molecules with the A aggregates suggests
acute-phase proteins, chemokines and cytokines like interleukin 1 a possible link between classical complement pathway activation,
(IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF-), inflammation and pathological aggregation of A. A decrease in
and transforming growth factor (TGF-). These molecular C1q levels has been reported in cerebrospinal fluid (CSF) of AD
mediators of inflammation have been linked with a series of patient and this result contrasts with an increase of C1q lev-
concomitant deleterious and beneficial effects (Figure 2). els in the CNS (Smyth et al., 1994). In vitro studies revealed
that C1q recognizes fibrillar and aggregated forms of A142
THE COMPLEMENT SYSTEM and A140, but not the monomeric forms. The C1q receptor
The complement system is an important innate and adaptive is expressed in microglia, which contributed to the belief that the
immune response effector. This system is composed of a number increase of this molecule in AD patient brains could affect the
of proteins and proteases that are activated in cascade (Forneris phagocytosis of A. However, in primary microglia rat culture
et al., 2012), and it appears to have a fundamental role in neu- studies, exposure to A142 and a nanomolar concentration of
rodegenerative diseases. Overall, the complement system uses the C1q caused a decrease in the phagocytosis of A, compared to
C1q molecule, mannose-binding protein or the interaction with cultures exposed only to A142 (Webster et al., 2000). A similar
the C3 multifunctional protein to recognize certain molecular result was observed in a transgenic mouse model, which expressed
patterns on pathogens. C3 activation recruits cells with phago- mutated hAPP and an absence of C1q expression (APPQ/ ).
cytic activity, and Membrane Attack Complex (MAC) is formed These mice showed no change in the amount of A aggregates,
by binding C5C9 (Ricklin et al., 2010). In adaptive immune but a decrease in glial cells activation was observed (Fonseca
et al., 2004), thus establishing that C1q importantly contributes
to microglial activation.
Microglia cells also produce C3. When these cells are
exposed to A synthetic peptides, their activation can be
observed as well as an increase in C3 synthesis to 5-to 10
fold (Haga et al., 1993). When this molecule is inhibited,
in the brain of an hAPP transgenic model, by the overex-
pression of the soluble form of the protein related to the
complement receptor (sCrry), a 2- to 3-fold increase in A
deposits formation was observed in one-year-old hAPP/sCrry
mice, which was accompanied by extensive neurodegenera-
tion (Wyss-Coray et al., 2002). APP/C3/ double trans-
genic generation confirmed that the molecule modulated the
microglia phenotype, and promotes A degradation (Maier et al.,
2008).
Complement receptor 1 (CR1) is expressed in cells with
phagocytic activity, C3b and C4b are CR1 ligands, and their
binding facilitates phagocytosis. Genome-wide association stud-
FIGURE 2 | Neuronal damage and A deposition triggers microglial
ies (GWAS) in AD patients have shown a direct relationship
and astrocytes activation and the generation of inflammation
molecular mediators. The acute production of molecules of the between CR1 gene variants with cognitive impairment in patients
complement system (C1q, C3, and C5), pro-inflammatory cytokines (IL-1, and an increase in amyloid plaque formation (Chibnik et al.,
IL-6, TNF-), chemokines (CCL2, MIP-1, MIP-1, and IL-8) mediate the A 2011).
clearance. However, in a chronic stage these molecules could promote an The anaphylatoxin (C5) has been linked to excitotoxicity and
increased expression and alteration of APP processing, A deposition, Tau
phosphorylation and neurodegeneration. Also, another effect of glial cells
apoptosis activation in the CNS, which is believed to play an
includes the generation of NO that promotes oxidative stress. The important role in the development of neurodegenerative diseases.
inflammatory microenvironment favors the production of COX-2 in neurons This molecule also promotes chemotaxis and glial cells activa-
that leads to apoptosis. In contrast, it has been proposed that glial cells tion. In AD animal models, the use of the C5a receptor antagonist
could mediate neuronal survival, by the production of TGF- and (C5aR or CD88) reduces the amount of A aggregates and hyper-
neurotrophic factors (BDNF and NGF), but the disease progression results
in failure to repair neurons.
phosphorylated tau protein (Fonseca et al., 2009; Ager et al.,
2010). It appears that the complement system activation in AD

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

might have beneficial effects for A clearance; however, this acti- resulted in significant gliosis, a decrease in A deposits in
vation could eventually become deregulated and favor neurotoxic TgCRND8 mice brains due to phagocytic marker upregula-
effects by promoting unwanted inflammation. For these reasons, tion in glial cells and increasing microglial A phagocytosis.
more studies are required to understand the changes affecting the IL-6-induced neuroinflammation, and has not any effect
complement system in AD development. on APP- processing in TgCRND8 mice, which sug-
gests that reactive gliosis, could have a beneficial effect
CYTOKINES in early stages of disease by promoting A elimination
Immune system cells are able to produce cytokines, which are sol- (Chakrabarty et al., 2010).
uble proteins that mediate inflammation. In the CNS, cytokines
are produced by microglial cells and astrocytes and play a key TNF-
role in CNS development during the embryonic stages. Cytokines TNF- is a cytokine that can have beneficial or harmful effects on
are involved in the inflammatory processes of neurodegenerative different neurons. This cytokine stimulates NF-B transcription
diseases. In AD, these proteins may be important in the devel- factor which, induces the pro-inflammatory molecules expres-
opment of the pathology. Studies of AD patient tissues and CSF sion, and promote the synthesis of neuronal survival factors
have shown elevated levels of pro-inflammatory cytokines such as such as calbindin, manganese superoxide dismutase enzyme,
IL-1, IL-6, IL-10, TNF-, and TGF- (Blum-Degen et al., 1995; and anti-apoptotic Bcl-2 protein (Wajant et al., 2003; Kamata
Tarkowski et al., 2002; Mrak and Griffin, 2005; Jiang et al., 2011). et al., 2005). This cytokine can stimulate microglia glutami-
The increase of these cytokines is strongly related to microglia nase to release glutamate, thus generating excitotoxicity (Takeuchi
activation by exposure to A aggregates (Meda et al., 1999). et al., 2006) and promoting the development of neurodegener-
Animal models that overexpress the mutant hAPP protein have ative diseases. In AD, the direct role of this cytokine remains
shown a direct relationship between the amount of A aggregates uncertain; however, TNF- could be associated with an increased
and elevated levels of TNF-, IL-6, IL-12, IL-1, and IL-1 (Patel - and secretase enzyme expression (Blasko et al., 2000; Liao
et al., 2005). In particular, studies have been performed seeking et al., 2004). In vitro models have shown that TNF- directly
the relationship between each cytokine with AD. stimulates BACE1 expression, thus favoring APP processing
(Yamamoto et al., 2007). The use of soluble TNF- inhibitors
IL-1 had a protective effect on APP deregulation by decreasing amy-
IL-1 is known to be able to induce APP- mRNA expression in loid aggregate formation and attenuating the cognitive impair-
endothelial cells (Goldgaber et al., 1989), which suggests that IL- ment observed in 3xTgAD mice exposed to chronic peripheral
1 increasing in AD patients could be linked to A formation. inflammation (McAlpine et al., 2009). However, a long-term
In a study with AD patients, it was also proposed that IL-1 was suppression of the TNF- receptor signaling pathway can sup-
produced by microglial cells surrounding NPs and this cytokine press the microglial ability to efficiently remove A aggregates,
could promote S100 synthesis in astrocytes (Griffin et al., 1989). thus favoring its aggregation at early stages (Montgomery et al.,
Subsequently, it was discovered that IL-1 was a contributing fac- 2011).
tor to initiate dystrophic neurite formation in A diffuse deposits
(Griffin et al., 1995). Similarly, the exposure of primary cultures TGF-
of rat cortical neurons to S100 promotes dystrophic neurite TGF-; is another cytokine with pleiotropic functions, which
formation and APP- mRNA expression (Li et al., 1998). Thus, has an anti-apoptotic function and promotes neuronal survival.
IL-1 might promote the A formation and neuronal degenera- It is believed that this cytokine is involved in neurodegenera-
tion through S100 present in reactive astrocytes. Additionally, tive diseases (Krieglstein et al., 2002; Konig et al., 2005). It has
the increase in IL-1 in AD patients might promote an increase been reported an increase in TGF-1 levels in the brain of AD
in p38-MAP kinase activity, which could lead to Tau hyperphos- patients (Flanders et al., 1995). Animal models (hAPP/TGF-1)
phorilation (Sheng et al., 2000; Li et al., 2003). IL-1 signaling have shown that TGF-1 overexpression promotes amyloidogen-
blockade decreases GSK-3 activity and Tau phosphorylation esis in the meninges and cerebral vasculature at early stages (23
and promotes neurogenesis through the Wnt/-catenin pathway months) (Wyss-Coray et al., 1997). By contrast, in hAPP/TGF-
(Kitazawa et al., 2011). However, it has been recently suggested 1 transgenic mice parenchyma, there is a decrease in amyloid
that IL-1 could promote A removal (Matousek et al., 2012). plaque formation, which correlates with microglial activation
(Wyss-Coray et al., 2001). In AD patients, although TGF levels
IL-6 are elevated, there is a significant decrease in the expression of
IL-6 is produced by microglial cells and is involved in the the TGF- receptor type II (TRII); this decrease may suggest
immunoreactivity present in patient tissues with clini- that the signaling pathway mediated by this receptor has signif-
cal dementia (Hull et al., 1996). Similarly to IL-1, IL-6 icant neuroprotective functions and could be altered during the
promotes APP- expression (Ringheim et al., 1998) and development of the disease (Tesseur et al., 2006).
could also contribute to NFT formation by inducing Tau In summary, the role played by cytokines remains controver-
phosphorylation through cdk5/p35 pathway deregulation sial. On one hand, cytokines might favor microglial and astrocytic
(Quintanilla et al., 2004). However, IL-6 overexpression activation to promote A phagocytosis and neuronal survival. On
has been observed in the brain of two hAPP transgenic the other hand, chronic cytokine production has been described
models (TgCRND8 and Tg2576). This overexpression as contributors of neurodegeneration.

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CHEMOKINES because they cause vasodilation, thus allowing the immune sys-
Chemokines are small proteins whose principal function is tem cell transport to operate at the target site (Williams, 1978).
to attract monocytes, macrophages, lymphocytes, neutrophils, COX-1 and COX-2 isoforms are expressed in mammalian brain.
basophils, eosinophils, and dendritic cells toward sites in which COX-1 is expressed in microglia and neurons located in the pons
an inflammatory response is required. Chemokines function and spinal cord that perform autonomous and sensory func-
through the activation of their G protein-coupled receptors and tions. COX-2 occurs in glutamatergic neurons of hippocampus
are divided into four families, CXC, CC, C, and CX3 C (Wells et al., and cortex and is thought to be involved in the modulation of
1998; Cyster, 1999). plasticity processes and long-term potentiation (Yamagata et al.,
Astrocytes and microglial cells, are the main producer of 1993; Breder et al., 1995); in pathological conditions, the pres-
chemokines in the CNS, and their receptors are observed to be ence of COX-1 in the CNS has been linked to inflammation
present in neurons. Chemokines and their receptors also par- development, whereas COX-2 is associated with neurotoxicity.
ticipate in the CNS immune response and promote lymphocyte Microglia surrounding the NPs in AD patient shows a high
migration from the lymphoid organs in order to establish the expression of COX-1, which suggests inflammation (Yermakova
inflammatory process (Ransohoff et al., 1996). et al., 1999). On the other hand, COX-2 expression in the
Evidence of the participation of chemokines in AD is the hippocampal CA3 region appears to be related with the quan-
presence of monocyte chemotactic proteins (MCP-1 or CCL2) tity of NPs and NFTs and the observed cognitive impairment
and chemokine receptors CCR3 and CCR5 in reactive microglia (Ho et al., 2001). COX-2 overexpression in a triple transgenic
that surround senile plaques of AD patients. By contrast, the model (hAPP/PS1/hCOX-2) has resulted in an increase in active
macrophage inflammatory protein 1 (MIP-1) is located mainly Caspase-3 immuoreactivity and retinoblastoma protein phospho-
in neurons, and MIP-1 is located primarily in astrocytes that rylation (S795 -pRb). The Rb protein regulates the G1 phase of
surround the plaques (Ishizuka et al., 1997; Xia et al., 1998). the cell cycle, but S725 phosphorylation suppresses cell growth.
The differential expression of chemokines and their receptors In vitro studies revealed that hCOX-2 overexpression in pri-
promotes glia-neuron communication to establish a local inflam- mary cultures of cortical and hippocampal neurons derived from
matory response, which could favor A phagocytosis in early transgenic mice, accelerates the apoptotic damage induced by
stages of AD. Similarly, it is known that this inflammation con- A, causing cell cycle abnormalities (Xiang et al., 2002a). COX-
tributes to Tau pathology and thereby accelerates the disease 2 also promotes amyloid plaque formation in parenchyma and
progression (Zilka et al., 2012). increases prostaglandin E2 production. This increased plaque for-
Chronic inflammation in AD promotes the increased chemo- mation, correlates with an increase in amyloid peptide formation
taxis of phagocytic cells, thus favoring microglial recruitment (A140 and A142) through the secretase activation without
around A aggregates (Yamamoto et al., 2005). A recent study affecting the APP expression levels (Xiang et al., 2002b). Studies
of CSF from AD patients revealed increased CCL2 levels, which performed in a mouse model using COX-2/ deficient mice
correlated with cognitive decline (Westin et al., 2012). Moreover, demonstrated that the inflammatory response mediated by A
because of A aggregation, an increase in IL-8 production was diminished, which suggested that COX-2 inhibition could
(CXCL8) is generated in neurons, which correlates with an be an important target to be use for therapy (Choi and Bosetti,
increase in the formation of brain-derived neurotrophic factor 2009).
(BDNF) (Ashutosh et al., 2011). The analysis of post-mortem brain tissue from AD patients
The presence of A, in the microvasculature, promotes demonstrated that the maximum immunoreactivity for COX-2
the release of IL-8, MCP-1, MIP-1 MIP-1, and MIP- and ppRb occurred in the early stages of the disease (Braak),
1 chemokines, and thereby promotes monocyte differen- before occur the maximum astrocytic and microglial activation.
tiation into macrophages and their migration through the Contrary to in vitro observations, the post-mortem tissue analy-
blood-brain barrier (Fiala et al., 1998). CSF analysis from sis did not support the direct relationship between the microglial
AD patients also showed an increase in MCP-1 and IL- and astrocytic activation with the neuronal COX-2 and ppRb
8 chemokines levels (Galimberti et al., 2003; Correa et al., expression in AD (Hoozemans et al., 2005).
2011). Similarly, in vitro models have demonstrated the migra- Currently, the cause of alterations in COX-2 levels dur-
tion ability of lymphocytes (CD4+ and CD8+ ) through the ing different stages of AD, remains unknown. However, it
blood-brain barrier (Man et al., 2007) because of an increased has been suggested that inflammation in the early stages of
MIP-1 level. AD could promote such alterations, and IL-1 could pro-
In conclusion, chemokines in the CNS are able to promote mote an increase in COX-2 expression and PGs production
local and peripheral immune system cell migration in order to (Hoozemans et al., 2001).
establish an immune response. In AD, it has been proposed that
the chronic production of chemokines contributes to disease NITRIC OXIDE
progression. NO is a molecule that contributes importantly in cell signal-
ing. In the presence of oxygen, L-arginine, is converted to L-
CYCLOOXYGENASES citrulline and release NO. Nitric oxide synthase (NOS) is the
Cyclooxygenases (COX) are enzymes responsible for converting enzyme responsible for catalyzing this reaction, and it occurs
arachidonic acid to H2 prostaglandin, which is a PG precursor. in three isoforms. In the CNS, the neuronal isoform (nNOS)
In general, these lipidic molecules are involved in inflammation is widely distributed in neurons, astrocytes and blood vessels.

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

The endothelial isoform (eNOS) is located in the hippocam- studies. This section will also analyse the use of active and passive
pal pyramidal neurons, endothelial cells and some astrocytes. immunotherapy as a therapeutic strategy for AD (Table 1).
The expression of the inducible isoform (iNOS) is typically
low but is increased in microglia and astrocytes during neuro- ANTI-INFLAMMATORY DRUGS
inflammation. Under physiological conditions, it is believed that NSAIDs are a heterogeneous group of drugs that share a common
NO regulates the release of neurotransmitters and hormones and mechanism of action, which involves COX-1 and COX-2 enzymes
promotes cell survival and long-term potentiation. However, high inhibition either selectively or non-selectively (Vane and Botting,
levels of NO are generated in inflammatory conditions, which 1987). These enzymes catalyze arachidonic acid conversion to
might contribute to synaptic transmission dysfunction, protein prostaglandin H2 (PGH2 ), which is subsequently converted into
and lipid oxidative damage, excitotoxicity, and neuronal death various PGs (PGE2 , PGD2 , PGF2 , and PGI2 ) and thromboxane
(Liu et al., 2002; Bishop and Anderson, 2005; Calabrese et al., (TX) (Dubois et al., 1998).
2007). PG and TX synthesis increases in occurrence of tissue dam-
Tissue and neuronal analyses of AD patients have revealed age, acting as inflammation mediators, increasing blood flow and
that A is able to promote NOS expression and NO produc- vasodilation in the damaged tissue and increasing microvascular
tion in microglia cells and reactive astrocytes (Goodwin et al., permeability (Flower et al., 1976).
1997; Wallace et al., 1997; Akama et al., 1998). A also pro- The results of several epidemiological studies designed to iden-
motes the pro-inflammatory cytokines IL-1 and TNF- lib- tify AD risk factors have shown that prolonged use of NSAID
eration which contribute to NO and peroxynitrite formation could reduce AD risk. The following are the results from some of
(Rossi and Bianchini, 1996; Combs et al., 2001) and cause pro- the most representative studies conducted on different worldwide
tein and lipid modifications, mitochondrial damage, apoptosis populations.
and promote A formation, increasing the -secretase com- The Sydney Old Persons Study showed that NSAID use, is sig-
plex activity (Torreilles et al., 1999; Keil et al., 2004; Guix nificantly lower in subjects who developed AD than in those
et al., 2012). Under normal conditions, NO is synthesized in who did not develop any type of dementia during the study
the microvasculature and regulates -secretase activity which period (Broe et al., 2000). Notably, NSAID use is not associ-
participate in APP processing (Austin et al., 2010). NOS2 also ated with any other type of dementia except AD. This result
favors A elimination by regulating MMP-9/TIMP-1 expression, could suggest that NSAID use in AD may act through a different
which is a key enzyme that degrades amyloid (Ridnour et al., mechanism from their properties as cyclooxygenase inhibitors.
2012). In addition, it has been shown that chronic NO for- The Rotterdam study (InT Veld et al., 2001), Multi-Institutional
mation may alter insulin-degrading enzyme activity (Kummer Research Alzheimers Genetic Epidemiology Study (Yip et al.,
et al., 2012). NO synthesis during AD development could 2005) and Canadian Study of Health and Aging (CSHA) (Cot
also contribute to NFT formation. In co-cultures of astrocytes et al., 2012) also observed an association between the NSAID use
and hippocampal neurons of rats, exposure to A2535 was and a reduced AD risk. Szekely et al. conducted a meta-analysis
found to increase NO levels, which correlated with increased of six studies (the Baltimore Longitudinal Study of Aging, Cache
hyperphosphorylated Tau protein. Interestingly, the use of a County Study, CSHA, Cardiovascular Health Study, Framingham
NOS inhibitors reduced Tau phosphorylation levels (Saez et al., Heart Study and Monongahela Valley Independent Elders Study)
2004). and reiterated the association between the NSAID use and a
reduced AD risk (Szekely et al., 2008). However, some studies have
INFLAMMATION MODULATOR TREATMENTS: failed to replicate this association. The Longitudinal Aging Study
THERAPEUTICS IN AD Amsterdam observed a reduction in AD risk associated with the
In the early 1990s, studies began to emerge relating the inflamma- use of aspirin alone and observed no association between AD
tion process with AD. Studies such as those of Fillit et al. (1991) risk and other NSAIDs (Jonker et al., 2003). Bendlin et al. also
showed that certain pro-inflammatory cytokines were elevated in observed no significant differences in the results of neuropsycho-
AD patients. logical memory and learning tests between NSAIDs users and
Epidemiological studies (Li et al., 1992) indicates that sub- non-users (Bendlin et al., 2010).
jects with arthritis have a lower prevalence of AD, after which it Other studies have observed controversial results, such as
was proposed that this negative association could be related to Fourrier et al. who observed an association between NSAIDs use
the chronic use of anti-inflammatory drugs (Dickson and Rogers, and a decrease in Mini-Mental State Examination (MMSE) scores
1992). From these and other results, these drugs began to be pro- (Fourrier et al., 1996). Similarly, Breitner et al. reported a greater
posed as a new therapeutic approach for AD treatment. Currently, incidence of AD among NSAIDs users compared with controls
numerous epidemiological studies, experimental in vitro and (Breitner et al., 2009).
in vivo models and clinical trials have been designed to elucidate Martin et al. obtained equally unfavorable results when testing
the relationship between modulators of inflammation and AD. the effect of naproxen and celecoxib in older adults with a family
Typically, anti-inflammatory agents are divided into non- history of AD (Martin et al., 2008). In this study, subjects treated
steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. with naproxen and those treated with celecoxib scored lower on
This section will review the mechanisms of action of both types the MMSE than subjects treated with placebo, which suggested
of anti-inflammatory agents and their role in AD and the results a detrimental effect of the use of these drugs on cognitive per-
of some of the most relevant epidemiological and experimental formance. Aisen et al. tested the effect of rofecoxib and naproxen

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

Table 1 | Inflammation modulator treatments and their effects in animal models and clinical trials.

Therapy Drug Effects in animal models and clinical trials

Naproxen No beneficial effects reported. High frequency of adverse effects in drug-treated group, in clinical trials

Celecoxib Drug-treated group was found to score lower than placebo-treated group in cognitive tests, in clinical trials

Rofecoxib No beneficial effects reported. High frequency of adverse effects in drug-treated group, in clinical trials
NSAIDs

Indomethacin In mice treated with this drug, lower A levels in cortex and hippocampus were observed

Mefenamic acid Mice treated with this drug performed as well as healthy controls in cognitive tests

Triflusal In mice treated with this drug, a decrease in microglial and astrocytic activation, and a decrease in cytokine
levels were observed

Ibuprofen Mice treated with this drug performed as well as healthy controls in cognitive tests. However, an increase
in soluble A levels and some behavior disturbances were observed in the drug-treated group

Corticosterone/ Cortex, cerebellum and brainstem from mice treated with this drug showed increased expression of APP
Glucocorticoids

Dexamethasone and beta-secretase, A deposition, tau aggregation and caspase 3, cytochrome c, IL-1 and TNF- levels.
Drug-treated mice were found to score lower than placebo-treated mice in memory tasks

Prednisone No beneficial effects reported. Higher frequency of behavior disturbances was observed in the drug-treated
group, in clinical trials

A peptides In mice, this therapy was able to prevent synaptic loss. Clinical trials have shown some beneficial effects in
subjects who formed antibodies, but the incidence of meningoencephalitis as a side effect is notably high
Immunotherapy

Anti-A antibodies In treated mice, a reduction in synaptic loss and number of dystrophic neurites and an increase in the
number of dendritic spines have been reported. In clinical trials, no beneficial effects have been reported

Tau peptides Prevention of cognitive decline and a decrease in the number of NFTs has been reported in mouse model
studies

Anti-tau antibodies A decrease in the number of NFTs has been reported in treated mice

Although most of these treatments have been successful in animal models, these beneficial results have not been reproduced in clinical trials, and even have been
cause of detrimental effects.

on patients with mild to moderate AD (Aisen et al., 2003). The transgenic mice (Tg+) performance in Morris test and a condi-
study, which lasted one year, showed no significant differences in tioning test (Coma et al., 2010). Although Triflusal had no effect
the performance of subjects treated with rofecoxib or naproxen or on reducing NP size (NPS) or number, it reduced the amount
placebo. In addition, subjects in NSAID-treated groups reported of activated astrocytes and microglia and IL-1 and TNF- levels
a high frequency of adverse effects such as fatigue and dizziness in the hippocampal CA1 region and entorhinal cortex. Van Dam
and had a significantly higher incidence of hypertension. Another et al. observed similar results in TgAPP23 mice after treatment
study with rofecoxib, conducted in patients with mild cognitive with Ibuprofen (Van Dam et al., 2010).
impairment (MCI), suggested a deleterious effect of rofecoxib In the animal model (5XFAD), which overexpressed the
(Thal et al., 2005). Swedish double mutation (K670N, M671L), Florida mutation
The results of AD animal model studies appear to support (I716V), London mutation (V717I), and double mutation in PS1
the hypothesis that the use of NSAID is beneficial, not only as (M146L and L286V), treatment with ibuprofen for 3 months
a method of preventing the disease, but also as a therapeutic resulted in a reduction of the inflammatory response. However,
strategy. This support was observed in Tg2576 (Swe-APP) trans- it is notable that there was an increase in soluble A42 levels and
genic mice treated with indomethacin, which showed a marked there was some changes in behavior, thus questioning whether
decrease in A levels (A140 and A142 ) in both cortex and anti-inflammatory drug use may actually be beneficial for AD
hippocampus (Sung et al., 2004). treatment (Hillmann et al., 2012).
Subsequently, Joo et al. showed that mice treated with mefe- Whereas inflammation is a neuropathological feature always
namic acid for 3 weeks after being treated with A142 or express- present in AD, and inflammatory processes significantly con-
ing Swe-APP, re-established their performance in the Morris tribute to cell damage in this disease, previous studies performed
water maze test in a comparable way to the vehicle-treated in vivo and in vitro suggest that NSAIDs participation in
group (Joo et al., 2006). Coma et al. obtained similar results in AD occurs not only through an anti-inflammatory mechanism
Tg2576 transgenic mice treated with Triflusal (a NSAID from the but also by modulating A synthesis and removal in the
salicylate family but a non-aspirin derivative), thus re-establishing CNS. Several studies have shown that NSAIDs stimulate the

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

non-amyloidogenic APP-processing pathway (Avramovich et al., have a pro-inflammatory effect, thus favoring IL-1 and TNF-
2002), decrease -secretase levels (Sastre et al., 2006), and reduce expression (Macpherson et al., 2005).
the A formation (Hirohata et al., 2005). These studies indicates that the mechanisms that might
Although animal models appear to show that NSAIDs are a associate glucocorticoids with an increase in AD risk are
promising therapeutic option, currently, no clinical trials con- related with the increasing expression of proteins involved in
ducted with these drugs have achieved favorable results in AD A synthesis (APP and -secretase) or promoting apoptosis
patients. (Cotman and Anderson, 1995).
In humans, there is only one clinical trial investigating the
GLUCOCORTICOIDS effect of glucocorticoids in the treatment for AD, the trial investi-
Similar to NSAIDs, glucocorticoids have potent anti- gate the used of a daily dose of prednisone or placebo for 1 year
inflammatory effects, which have made them strong candidates (Aisen et al., 2000). There were no significant differences in the
for AD treatment. Basically, the mechanism of action of glu- cognitive performance of AD subjects treated with prednisone or
cocorticoids is based on their ability to bind to its receptors placebo at the end of treatment; however, the prednisone-treated
(Glucocoticoid Receptor, GR), which is observed in the cyto- subjects showed a higher frequency of behavioral disturbances
plasm in its free form, which translocates into the nucleus after compared to controls.
binding to one of its ligands. When GR locate at the nucleus, it In general, there is little evidence to suggest the neuroprotec-
binds to certain nucleotide sequences, glucocorticoid response tive or therapeutic role of glucocorticoids in AD; in contrast, there
elements (GREs), which are located in the promoter region of a is extensive evidence of a possible neurotoxic role. Whereas it is
variety of genes. possible that under certain conditions these substances are actu-
Depending on the type of GRE sequence to which it binds, ally neuroprotective, details of their mechanism of action should
GR will positively or negatively regulate gene expression (Beato be extensively evaluated in AD before a clinical testing protocol
et al., 1989). The importance of this binding in the inflamma- can be considered.
tory process is that some genes which GR binds to and activates,
have anti-inflammatory effects such as annexin-1 (lipocortin-1), IMMUNOTHERAPY
interleukin 10 and NF-B inhibitor (IB-) (Barnes, 2006). In Currently, there is no consensus among researchers regarding
addition, it has also been suggested that glucocorticoids interact what triggers AD pathophysiology or which events are causes
directly with A. and which are bodily responses to counteract the damage caused
The study of post-mortem AD brains showed a decrease in by the disease. This problem has also been raised regarding
the presence of NPs in subjects under chronic treatment with inflammation.
corticosteroids. No significant differences were observed in the Whereas therapies using NSAIDs and glucocorticoids were
number of NFTs. This study also reported no association between designed based on the idea that the immune response in AD has
chronic treatment with NSAIDs and the number of NPs (Beeri an adverse effect (Blasko et al., 2004) or may be a causal factor
et al., 2012). (McGeer and McGeer, 1995), there are other approaches which
Despite its anti-inflammatory effect, the use of glucocorticoid suggest that the immune response may be beneficial because it
as a therapeutic strategy in the treatment of AD is controver- attempts to counteract the deleterious effects of A oligomers and
sial, because numerous studies have associated increased levels Tau aggregation.
of glucocorticoids (cortisol), to an increased AD risk. In 1994, Immunotherapy is one of the therapeutic strategies designed
Swaab et al. measured cortisol levels in post-mortem samples under these bases because it is underlying on promoting the
of CSF and observed an 83% increase in AD subjects compared immune response against the altered molecules that are present
to healthy controls (Swaab et al., 1994). These results coincide in the most distinctive histopathological lesions of the disease
with the results of Laske who observed significantly higher lev- (NPs and NFTs) and destroy them. This section will review the
els of serum cortisol in AD patients compared with age-matched types (anti-A and anti-Tau immunotherapy) and some results
healthy controls (Laske et al., 2009). of immunotherapeutic studies with AD patients.
The majority of animal model experiments does not sup-
port the use of corticosteroids as a therapeutic strategy for AD ANTI-A IMMUNOTHERAPY
and suggests that these drugs promote the development of the Animal studies in which the anti-A immunotherapy strategy has
neuropathological features of this disease. been tested have been promising. Buttini observed that either
The treatment of rats with glucocorticoids (corticosterone and active (using four different A sequence fragments) or passive
dexamethasone) induces an increase in APP expression in cortex, immunotherapy (using 3D6 anti-A and 12B4 antibodies) pre-
cerebellum, and brain stem (Budas et al., 1999), thus suggest- vent the loss of synapses in PDAPP transgenic mice (Buttini et al.,
ing an adverse effect. Additionally, there is an increase in A 2005).
formation because of the increased APP and -secretase levels. The application of a single 3D6 anti-A dose in Tg2576 mice
These glucocorticoid levels also correlate with Tau accumulation demonstrated that there was no reduction in the number of NPs;
(Green et al., 2006), memory, and learning impairment (Yao et al., nevertheless, there was a reduction in the number of dystrophic
2007) and increased levels of caspase 3 and cytochrome c, which neurites (Rozkalne et al., 2009). On the other hand, the appli-
indicates the presence of a pro-apoptotic enviroment (Li et al., cation of this antibody in PDAPP mice showed an increase in
2010). Finally, high levels of corticosterone in hippocampal cells the number of dendritic spines, which suggests that this anti-A

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

immunotherapy approach, can increase neuronal plasticity and These results indicate that immunotherapy, particularly anti-
could contribute to the recovery of neural circuits. Subsequently, A active immunotherapy, could be advantageous when a strategy
the effect of passive immunotherapy was studied with 7B6 anti- that minimizes its adverse effects is achieved. Further studies are
A antibodies in A APPswe/PS1dE9 mice (Spires-Jones et al., also required with anti-Tau immunotherapy to evaluate whether
2009; Liu et al., 2011). The authors observed that mice had a this therapy could be functional in the future.
higher density of mono-aminergic axons in both the cortex and
hippocampus. Immunotherapy using anti-A CAD106 antibod- CONCLUSION
ies in different transgenic mouse models for APP (APP23 and Currently, several genetic and epidemiological studies have pro-
APP24) showed a reduction in the presence of A in both models vided an overview of the inflammatory mechanisms involved
(Wiessner et al., 2011). in AD. Although the molecular basis of the disease remains
In humans, some results suggest that anti-A active unknown, the inflammation induced by A has an important
immunotherapy could be beneficial; however, the frequency role in the neurodegenerative process. The inflammatory process
of adverse effects has been too high. In a study of active itself is driven by microglial and astrocytic activation through the
immunotherapy using A142 pre-aggregating (AN1792) in induction of pro-inflammatory molecules and related signaling
combination with immunogenic adjuvant QS-21 (a saponin of pathways, thus leading to synaptic damage, neuronal loss, and the
vegetable origin) observed a slower cognitive decline in subjects activation of other inflammatory participants.
responding to the treatment (forming specific antibodies) (Hock Although, the role of amyloid as a potential initiator of inflam-
et al., 2003; Orgogozo et al., 2003). However, 10% of the partici- mation is not obvious, its accumulation exerts an indirect effect
pants developed cases of aseptic meningoencephalitis. A similar by activating caspases and transcription factors, such as NF-B
result was obtained in an additional group of patients who were and AP-1, which produce numerous inflammation amplifiers
evaluated after stopping the treatment due to the adverse effects (IL-1, TNF-, and IL-6). Pro-inflammatory cytokines, such as
observed. The monitoring of these patients included cognitive TNF- and IL-1 and IL-6, could act directly on the neuron and
testing and MRI scans to determine brain volume. Patients who induce apoptosis. Similarly, TNF- and IL-1 can activate astro-
were classified as antibody producers before the suspension of cytes, which could release factors that have the capacity to activate
the study were tested for the presence of antibodies using ELISA; microglia.
89% of patients had antibodies at the time of investigation. These Furthermore, APP, BACE1, and PSEN expression is governed
patients positive to antibodies production, performed better on by factors such as NF-B. The genes encoding these proteins have
cognitive tests than those treated with placebo, which suggests a sites in their promoter regions, which are recognized by NF-B; in
possible beneficial effect of the treatment. However, brain volume turn, the expression of these factors is upregulated by the presence
loss was identical for both groups (Vellas et al., 2009). of pro-inflammatory cytokines.
The high incidence of aseptic meningoencephalitis among Inflammatory mediators acting on neurons contribute to an
the subjects receiving active anti-A immunotherapy could increase in amyloid production and activate microglia-mediated
be attributed to an excessive pro-inflammatory response by inflammation. The microglia-neuron communication amplifies
T lymphocytes. Unfortunately, passive immunization with the production of factors that contribute to AD-type pathology.
bapineuzumab, (a humanized murine monoclonal antibody), However, the neural response is specific for the receptor type
showed no differences in cognitive performance in subjects expressed in the different neuronal populations. For example,
treated with bapineuzumab or placebo (Salloway et al., 2009). TNF- binds TNFR1, which activates the cell survival pathway
through NF-B and the apoptotic pathway through the activation
ANTI-Tau IMMUNOTHERAPY of caspases. Conversely, TNFRII signaling only activates NF-B.
Most of the research efforts into AD immunotherapy have This cascade is primarily mediated by the pro-inflammatory
focused on anti-A immunotherapy. However, some studies in cytokine IL-1, which is expressed by microglia cells. IL-1
animal models have also used anti-Tau immunization. may cause neuronal death via various pathways, which activate
Boutajangout et al. showed that immunotherapy with the microglia and consequently increase the release of IL-1, thus
complete 441 amino acids peptides of the human Tau protein generating a self-sustaining mechanism that is amplified by itself.
(hTau) prevented cognitive decline in an hTau transgenic mouse This slow but steady inflammation state, generated for long peri-
model, which expressed the hTau transgene (Boutajangout et al., ods in the brain eventually can destroy neurons and contribute to
2010). Boimel et al. immunized the Tau transgenic mice present- the clinical symptoms observed in the disease (Figure 1).
ing NFTs with phosphorylated Tau peptides. A 40% reduction in Finally, in accordance with all the above data, particularly
the number of NFTs was observed (Boimel et al., 2010). Chai because the results of the treatments used have been contra-
et al. studied the effect of passive immunotherapy for Tau in dictory so far and there are no clinical trials that shown that
JNPL3 and P301S transgenic mice. Using PHF1 and MC1 anti- anti-inflammatory treatments and the use of immunotherapy
bodies, the authors observed that the peripheral administration are completely safe or beneficial, it is necessary to develop and
of both antibodies significantly reduced Tau pathology compared implement new strategies for AD immunological treatments.
to controls (Chai et al., 2011). Although these results suggest that
anti-Tau immunotherapy could provide favorable results, no clin- ACKNOWLEDGMENTS
ical trial has been reported to date that evaluated the real effects This work was supported by a grant from SEP/CONACYT (No.
on humans. 157548).

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Meraz-Ros et al. Neuroinflammation in Alzheimer Disease

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