Arch. Pharm. Res.
DOI 10.1007/s12272-015-0648-x
REVIEW
Involvement of inflammation in Alzheimer’s disease pathogenesis
and therapeutic potential of anti-inflammatory agents
Sina Shadfar1 • Chul Ju Hwang2 • Mi-Sun Lim1 • Dong-Young Choi1
Jin Tae Hong2
Received: 4 May 2015 / Accepted: 8 August 2015
 The Pharmaceutical Society of Korea 2015
Abstract Alzheimer’s disease (AD) is the most common
form of dementia. It is characterized by beta-amyloid (Ab)
peptide fibrils, which are extracellular depositions of a
specific protein, and is accompanied by extensive neu-
roinflammation. Various studies have demonstrated risk
factors that can affect AD pathogenesis, and they include
accumulation of Ab, hyperphosphorylation of tau protein,
and neuroinflammation. Among these detrimental factors,
neuroinflammation has been highlighted by epidemiologic
studies suggesting that use of anti-inflammatory drugs
could significantly reduce the incidence of AD. Evidence
suggests that astrocytes, microglia, and infiltrating immune
cells from periphery might contribute to or modify the
process of neuroinflammation and neurodegeneration in
AD brains. In addition, recent data indicate that micro-
RNAs may affect neuroinflammatory responses in the
brain. This article focuses on supportive evidence that
neuroinflammation plays a critical role in AD development.
In addition, we depict putative therapeutic capacity of anti-
inflammatory drugs for AD prevention or treatment. We
also discuss pathogenic mechanisms by which astrocytes,
Sina Shadfar and Chul Ju Hwang have contributed equally.
& Dong-Young Choi
neochallenger@yahoo.co.kr
& Jin Tae Hong
jinthong@chungbuk.ac.kr
1
College of Pharmacy, Yeungnam University, 280 Daehak-ro,
Gyeongsan, Gyeongbuk 712-749, Republic of Korea
2
College of Pharmacy and Medical Research Center,
Chungbuk National University, 52 Naesudong-ro,
Heungdeok-gu, Cheongju, Chungbuk 361-763,
Republic of Korea
•
microglia, T cells and microRNA participate in AD and the
neuroprotective mechanisms of anti-inflammatory drugs.
Keywords Alzheimer’s disease
Amyloidogenesis

Anti-inflammatory
Beta-amyloid
Neuroinflammation
Introduction
Alzheimer’s disease (AD) is the most prevalent neurode-
generative disease and the most common form of dementia.
However, specific molecular mechanisms by which neu-
rons degenerate in AD brains remain unclear, and there is
no known way to halt or cure the neurodegeneration in AD.
It is estimated that about 10% of the population older than
65 years of age suffers from the disease. The number of
AD patients is predicted to reach 14 million in the United
States by 2050, with incidence of a million cases per year
(Choi et al. 2012c). This situation underscores the urgency
for the development of therapeutic or preventative inter-
ventions of AD.
The pathologic hallmarks of AD are senile plaques and
neurofibrillary tangles. Senile plaques are extracellular
deposits of amyloid plaques, which are mainly composed
of b-amyloid (Ab) 40 or 42. Ab is produced by sequential
proteolytic cleavage of amyloid precursor protein (APP) by
beta and gamma secretases. Mutations in the genes of
presenilin 1, presenilin 2 and amyloid precursor protein are
associated with the pathogenesis of the familial form of
AD, suggesting that dysregulations of APP processing and
Ab production are critical pathways of neurodegeneration
leading to dementia in AD (Leuner et al. 2007). Neu-
rofibrillary tangles are intracellular protein depositions of
hyperphosphorylated tau protein. Tau filaments accumulate
in dystrophic neurites as fine neuropil threads or as bundles
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of paired helical filaments in neuronal bodies, forming
neurofibrillary tangles that become extracellular ghost
tangles after the death of the neuron (Liu et al. 2005).
Deposition of tau protein in the brain causes loss of
synaptic function and finally neuronal death (Crespo-Biel
et al. 2012). The number and localization of neurofibrillary
tangles have been well correlated with the level of
dementia, while no such correlation has been demonstrated
for senile plaques (Giannakopoulos et al. 2003). Tau
pathology, therefore, appears to be cardinal to AD clinical
manifestations.
Many therapeutic targets have been identified and
studied for modification of neurodegeneration in AD
brains. These include neuroinflammation, oxidative stress,
Ab accumulation, tau pathology, neuronal loss, and
synaptic loss (Frautschy & Cole 2010). However, multiple
disease-modifying therapeutic attempts to date have failed.
For instance, passive or active immunization against Ab or
tau protein was conducted to attenuate burden of the pep-
tide, but this trial was not successful and even caused
severe adverse effects such as brain microhemorrhages in
some AD patients (Panza et al. 2012). Neuroinflammation
appears to play a critical role in AD pathophysiology and
has been considered a promising target for AD treatment,
although none of the anti-neuroinflammatory drugs is
clinically available for AD treatment. The role of neu-
roinflammation in AD pathogenesis was highlighted by
multiple epidemiological and animal studies in which
NSAIDs had substantial sparing effects on AD neurode-
generation (Etminan et al. 2003; McGeer & McGeer 2013).
Furthermore, neuroprotective effects of other classes of
anti-inflammatory drugs were demonstrated in models of
AD (Heneka et al. 2011).
In this article, we describe the association of neuroin-
flammation with the neurodegenerative process in AD and
the putative roles of microglia, astrocytes and T cells in AD
pathogenesis. In addition, we briefly describe the dysreg-
ulation of microRNA expression in AD brains and its
involvement in neuroinflammation and the process of AD.
Furthermore, we emphasize the therapeutic potential of
anti-inflammatory agents for treatment of AD and the
molecular mechanisms of their neuroprotective effects.
Neuroinflammatory responses in AD brains
Accumulating evidence indicates that there is a close link
between AD pathogenesis and neuroinflammatory cascades
in the brain. Neuroinflammation in AD brains might be
exerted by damaged neurons, highly insoluble Ab deposits,
and neurofibrillary tangles (Wenk 2003). Neuroinflamma-
tion manifests as astrogliosis, microglial activation, and an
increase in inflammatory cytokines such as interleukin
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(IL)-1b, IL-6, tumor necrosis factor-a (TNF-a) and trans-
forming growth factor-b (TGF-b). In addition, infiltration
of peripheral immune cells including T cells, macrophages
and others was detected in AD brains, and they may modify
the contribution of microglia and astrocytes to neuroin-
flammation. Recently, experimental results suggest that
microRNAs may affect neuroinflammatory reactions and
can be associated with AD pathogenesis (Thounaojam et al.
2013). Putative role of microglia, astrocytes and inflam-
matory stimulants such as IFN-c produced by T cells in AD
pathogenesis is depicted in Fig. 1, and contribution of
microRNAs to neuroinflammatory responses is described
in Fig. 2.
Astrocytes in AD brains
Astrocytes are the most abundant cells in the central ner-
vous system and constitute about 25% of the cerebral
volume (Morales et al. 2014). They have multiple physi-
ological functions including synaptogenesis, formation and
maintenance of blood-brain barrier, maintenance of ion
balance, maintenance of homeostasis, and turnover of
glutamate (Morales et al. 2014). However, astrocytes may
play a significant role in AD pathogenesis. Reactive
astrocytes are found in the post mortem brains of AD
patients and they are manifested by hypertrophy and
increased expression of glial fibrillary acidic protein
(Verkhratsky et al. 2010). Activated astrocytes are mostly
observed in areas with amyloid plaques (Nagele et al.
2004). Effects of astrogliosis on accumulation of Ab are
still debated, but Ab deposition (Mucke et al. 2000; Nils-
son et al. 2001) and tau phosphorylation (Padmanabhan
et al. 2006) are enhanced by a1-antichymotrypsin, an
acute-phase protein that is upregulated by activated astro-
cytes. Critical evidence for the role of astrogliosis in AD
pathogenesis is the correlation between the extent of
astrogliosis and cognitive impairment (Simpson et al.
2010). In normal brains, expression of BACE1 is exclu-
sively confined to neurons. However, astrocytes acquire the
ability to produce Ab and turn into Ab producers under
conditions of AD or chronic stress (Rossner et al. 2005). In
addition, expression of BACE1 in the astrocytes related to
Ab plaques is detected in several transgenic mouse AD
models (Hartlage-Rubsamen et al. 2003; Heneka et al.
2005a; Rossner et al. 2001).
Reactive astrocytes seem to neglect their neurosup-
portive functions, thus rendering neurons vulnerable to
excitotoxicity and oxidative stress (Steele & Robinson
2012). Furthermore, fragments of Ab promote inflamma-
tory response in the brain via calcineurin and NF-jB (Lim
et al. 2013). When astrocytes are stimulated by aggregated
Ab, they produce inflammatory cytokines (IL-1b and
TNFa) and reactive oxygen species. These cytokines could
Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential…

Fig. 1 The plausible roles of neuroinflammatory responses in AD pathogenesis. Inflammatory stress including environmental and genetic factors
might cause microglial and astroglial activation. Activated glial cells can release determental mediators including cytotoxic cytokines, reactive
oxygen species, nitric oxide, glutamate and byproducts of COX-2. Further, activated glial cells can contribute to accumulation of Ab via
expression of BACE1 and decreased phagocytosis of Ab. Therefore, anti-inflammatory drugs such as NSAIDs have been suggested to prevent
from AD neurodegenertion or delay AD progression in spite of their failure in multiple clinical trials

Fig. 2 MicroRNAs involved in inflammation and AD. MicroRNAs including miRNA-9, -34a, -125b, -146a, and -155 can be upregulated by
proinfalmmatory cytokine and Ab. These miRNAs are sensitive to NF-jB which increases levels of the miRNA transcription in AD brains.
MicroRNA-34a appear to downregulate TREM2 expression resulting in elevation of immune response. MicroRNA-125b and 146a reduce
expression of CFH which suppress the neuroinflammaotry response in the brains

be causative factors in the cognitive dysfunction of AD. In
addition, a secondary inflammatory response to IL-1b and
TNFa leads to astrocyte activation, with the long-term
effect of these cytokines being detrimental to the survival
of neurons (Morales et al. 2014).
Microglia in AD brains
Microglia are rich in the central nervous system (CNS), but
they are mostly concentrated in the hippocampus and
substantia nigra (Kim et al. 2000). These cells constitute
the major immune system in the CNS since they produce
cytotoxic mediators, perform phagocytosis, and behave
like antigen-presenting cells (Ousman & Kubes 2012;
Ransohoff & Engelhardt 2012). In addition, physiological
functions of microglia are essential for the development
and homeostasis of the CNS (Kettenmann et al. 2011). For
instance, they can secrete growth factors for the formation
of the CNS in the embryo and contribute to neurogenesis,
neuroprotection and synaptic pruning when they are in the
resting state (Morales et al. 2014).
In AD brains, microglia are prone to a pro-inflammatory
rather than phagocytic status (Mandrekar-Colucci & Lan-
dreth 2010). Furthermore, a pro-inflammatory environment
impaired microglial phagocytosis of Ab in vitro, while
anti-inflammatory factors enhanced Ab clearance (Koe-
nigsknecht-Talboo & Landreth 2005). Consistent with this,
deletion of PGE2 E prostanoid subtype 2 receptor in
APPSwe-PS1DeltaE9 mice markedly attenuated Ab plaque
deposition and enhanced phagocytosis (Liang et al. 2005).
In addition, neuroinflammation could contribute to tau
protein-mediated neuronal loss as shown in an animal

123

model for taupathy (Jaworski et al. 2011). Indeed, activated
microglia accumulated around tau-positive neurons, and
synapses were deleted before formation of neurofibrillary
tangles in P301S tau transgenic mice (Yoshiyama et al.
2007). Lipopolysaccharide (LPS)-induced peripheral
inflammation exacerbates tau pathology via CDK5-medi-
ated pathway in a transgenic model of AD (Kitazawa et al.
2005). Furthermore, a recent study showed that inflam-
mation induced by infection increased GSK3 activity in the
triple-transgenic mouse model of AD; this was associated
with a shift of tau from the detergent-soluble to the
detergent-insoluble fraction (Sy et al. 2011). Another study
demonstrated detrimental effects of activated microglia in
AD (Qiao et al. 2001). In this study, lipopolysaccharide
(LPS) was chronically infused in the lateral ventricle of
APPV717F mice with (apoE?/?) or without (apoE-/-)
expression of apolipoprotein E. Chronic LPS led to amy-
loid plaque-localized microglial activation, but significant
LPS-mediated acceleration of amyloid deposition was seen
only in APPV717F-apoE?/? mice, suggesting that experi-
mental induction of microglial activation by chronic
administration of LPS can accelerate amyloidosis in a
transgenic mouse model of AD in the presence of apoE,
and supporting the idea that activated microglia exacerbate
cerebral amyloidosis.
Activated microglia secrete multiple cytokines and
chemokines such as IL-1b, IL-6, TNF-a, IL-8, TGF-b, and
macrophage inflammatory protein-1a (MIP-1a), and the
levels are altered in AD patients compared to control
(Sastre et al. 2006). Animal models of AD, including
Tg2567 mice, show elevated levels of TNF-a, IL-1b, IL-
1a, chemoattractant protein-1, COX-2, and complement
component 1q (Benzing et al. 1999; Matsuoka et al. 2001).
In addition, polymorphisms of proinflammatory cytokines
are associated with an increased risk of AD (Ribizzi et al.
2010; Solito & Sastre 2012).
Several studies showed that some molecules can mod-
ulate microglial activation and Ab phagocytosis by
microglia. CD40 ligand increased TNF-a production in the
Ab-stimulated microglia, promoting injury of primary
cortical neurons (Townsend et al. 2005). In addition, a
study showed that deletion of CD40 ligand gene in APP/
PS1 mice attenuated amyloid deposition and microgliosis
(Laporte et al. 2006). Overexpression of the proinflam-
matory cytokine-like molecule human S100B in the
Tg2576 mouse exacerbated cerebral b-amyloid accumula-
tion and promoted Ab-induced microglial activation (Mori
et al. 2010). TREM2 is expressed in microglia and is a
genetic risk factor for AD (Guerreiro et al. 2013). Studies
suggest that TREM2 risk variants have impaired function
of TREM2 and reduced phagocytic clearance of amyloid
proteins or cellular microglia in the central nervous system
(Jonsson et al. 2013). Deficiency of CCR2 in Tg2576 mice
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S. Shadfar et al.
increased Ab deposition and reduced microglial recruit-
ment into the brain, particularly phagocytic macrophages
(El Khoury et al. 2007).
Microglial activation presents a first line of defense in
the CNS, but it can contribute to neurodegeneration. Thus,
understanding the underlying mechanisms by which
microglia shift between these two opposite phenotypes
may allow us to minimize microglia-mediated neuronal
damage and find a way to treat neurodegenerative diseases
such as AD.
T-cell-mediated immune response associated
with AD
Strong Ab-reactive T cell responses are more common in
healthy elderly subjects and patients with AD than in
middle-aged subjects, suggesting that intrinsic T cell
reactivity to the self-antigen Ab may be linked to AD
susceptibility (Monsonego et al. 2003). In addition, T-cell
infiltration was detected in the brains of AD patients in
proximity with Ab deposition; this is also true in mice of
the brains of AD model (Monsonego et al. 2006; Togo
et al. 2002). Entry of peripheral T cells was dependent on
TNFa produced by microglia (Liu et al. 2010). Limited
expression of interferon (IFN)-c in the brain promoted
T-cell infiltration into the cerebral parenchyma and
microglia-mediated Ab clearance in the APP-transgenic
mouse (Monsonego et al. 2006). Further, the stimulation of
Ab-reactive T cells at sites of Ab plaques resulted in IFN-
c-induced chemotaxis of leukocytes and therapeutic
clearance of Ab (Fisher et al. 2010). In contrast, recent data
indicate that IFN-c produced by T-cells infiltrating the
brain in AD tend to elevate microglial activation, Ab
deposition and impaired cognitive functions, and these
effects were ameliorated by systemic administration of
anti-IFN-c antibody in mice with AD (Browne et al. 2013).
The role of T regulatory cells (Tregs) in AD brains has been
studied. The adoptive transference of Tregs significantly
ameliorates impaired cognition and reduces the Ab-deposits
and microglial activation in a mouse model of AD [25].
Moreover, higher Tregs function has been associated with
lower cognitive manifestation in AD patients [68]. Contrary to
Tregs, the current evidence indicates that inflammatory Th1
and Th17 CD4-positive T-cells play an important role in the
physiopathology of AD, favoring the disease progression
(Browne et al. 2013; Goldeck et al. 2013).
Taken together, the current evidence indicates that
inflammatory Th1 and Th17 CD4-positive T-cells play an
important role in the physiopathology of AD, favoring the
disease progression. Nevertheless, other important
encephalitogenic T-cell subsets that play important
inflammatory or anti-inflammatory roles in MS have not
yet been studied in AD. Furthermore, studies implementing
Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential…
the genetic deletion of specific subsets of inflammatory or
anti-inflammatory T-cells would be very helpful in order to
clarify the specific roles and relevance of these different
T-cell subsets in the development and progression of AD.
Therefore, similar to the case for PD, future efforts are
required to evaluate the participation of important T-cell
subsets (Gonzalez & Pacheco 2014).
MicroRNAs and AD
MicroRNA (miRNA) species can contribute to homeostatic
brain gene expression by regulating translation of specific
mRNAs. Among miRNAs, miRNA-146a is the most studied
small non-coding RNAs in the field of human neurobiology,
and this miRNA modulates the innate response, inflammation,
and the microglial activation state (Alexandrov et al. 2014).
This miRNA is selectively increased in affected brain regions
by AD (Lukiw 2007; Sethi & Lukiw 2009) and can be induced
by inflammatory cytokines and Ab, or combinations of these
factors (Lukiw et al. 2008). A significant increase of the levels
of miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155
was found in the cerebrospinal fluid of AD patients compared
with age-matched controls (Alexandrov et al. 2012). These
miRNAs are NF-jB-sensitive proinflammatory miRNAs,
upregulated in AD brains and associated with progressive
propagation of neuroinflammation (Guedes et al. 2013). In
addition, a recent study showed that a specific genotype of
miRNA-146a is associated with an increased risk of AD as
well as cognitive decline (Cui et al. 2014). Aberrant expres-
sion of miRNA-146a was also found in an animal model of
AD (Li et al. 2011). MiRNA-146a increased the inflammatory
responses in the brains by down-regulating complement factor
H and interleukin-1 receptor-associated kinase-1, which are
critical suppressors of innate immunity acting on the cerebral
inflammation response (Olivieri et al. 2013).
Apart from miRNA-146a, miRNA-34a might be related
to AD development by upregulating neuroinflammation in
the brain (Zhao et al. 2013). MiRNA-34a is a NF-jB-
sensitive miRNA and reduces TREM2 expression, result-
ing in increased immune response and decreased phago-
cytic responses (Bhattacharjee et al. 2014). Although the
analysis of miRNAs in AD is a relatively new research
area, the data reported so far strongly indicate that
inflammatory microRNAs could play a key role in AD.
Anti-inflammatory agents and their therapeutic
potentials for AD
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Multiple epidemiological studies suggest that long-term
usage of NSAIDs decreases risk of AD development,
delays dementia onset, slows down disease progression,
and mitigates severity of cognitive dysfunction (Andersen
et al. 1995; Breitner et al. 1994; Gasparini et al. 2004;
Stewart et al. 1997). NSAIDs significantly reduced beta-
amyloid (Ab) secretion from cultured cells and amyloid
peptide accumulation in the AD animal models (Gasparini
et al. 2004; Lim et al. 2001; Yan et al. 2003). Among
NSAIDs, ibuprofen and flurbiprofen potently ameliorated
Ab burden via modulation of c-secretase activity and/or
anti-inflammatory effect (Carreras et al. 2013). Ibuprofen
attenuated the level of both Ab accumulation and tau
phosphorylation, and improved cognitive function in the
triple transgenic mouse model of AD that develops Ab and
tau pathology (McKee et al. 2008). Flurbiprofen reduced
cognitive impairment and Ab deposition in AD animal
models (Kukar et al. 2007).
Beneficial effects of NSAIDs on AD experimental
models might involve inhibition of cyclooxygenase (COX),
which is the key regulatory enzyme of the eicosanoid
biosynthetic pathway producing a variety of pro-inflam-
matory mediators (Breitner et al. 2011). COX-2 is con-
sidered the most appropriate target for anti-inflammatory
drugs due to its induction by inflammatory stimuli, but
recent data indicate that COX-2 can mediate neuroprotec-
tion and that COX-1 is a major player in the neuroin-
flammatory process (Choi et al. 2009). COX-1 is
predominantly localized in microglia, and the enzyme
might be the major player in neuroinflammation. There-
fore, COX-1 suppression by NSAIDs could protect neurons
from immune-derived challenge in the early stages of AD
(Rogers et al. 1993; Sung et al. 2004). In contrast, brain
COX-2 is abundant in neuronal dendrites, where it is
essential for transduction of post-synaptic signals from
NMDA-type glutamate receptors (Kaufmann et al. 1997).
COX-2 inhibition by conventional COX-1/COX-2 dual-
inhibitors or by COX-2 selective inhibitors could thus be
deleterious to patients with these conditions (Breitner et al.
2011). Furthermore, a recent study demonstrated that
administration of a COX-1 selective inhibitor, SC-560, in
triple transgenic mice reduced neuroinflammation and
neuropathology and improved cognitive performance (Choi
et al. 2013). Besides inhibiting cyclooxygenase, NSAIDs
such as indomethacin (Netland et al. 1998) and flurbiprofen
(Prosperi et al. 2004) reduced microglial activation in AD
brains. The benefits of NSAIDs may result from a variety
of mechanisms independent of COX inhibition. For
example, researchers have shown that action mechanisms
of NSAIDs are related to modulation of c-secretase activity
(Weggen et al. 2003), inhibition of RhoA (Fu et al. 2007),
and activation of peroxisome proliferator-activated recep-
tor (PPAR)-c (Kummer & Heneka 2008).
Several randomized clinical trials have been performed
to assess the possible therapeutic efficacy of NSAIDs (Lee
123

et al. 2010). However, the outcomes from those trials were
disappointing (Table 1). Clinical trials with NSAIDs in
patients with established dementia did not significantly
attenuate progression of dementia (Soininen et al. 2007;
Thal et al. 2005). In a study with rofecoxib and naproxen,
the drugs were not able to halt or slow the progression of
AD (Aisen et al. 2003). Another study also showed that
naproxen and celecoxib were not able to prevent AD
development (Group et al. 2007). A randomized controlled
study showed that ibuprofen treatment had no effect on
worsening of cognition in AD patients (Pasqualetti et al.
2009). One study suggested that NSAIDs are even detri-
mental in later stages of AD pathogenesis (Breitner et al.
2011). A few studies demonstrated that NSAIDs are
effective only in the ApoE 34 carrier subpopulation
(Hayden et al. 2007; Szekely et al. 2008). It is well known
that the ApoE 34 allele confers an inflammatory state in the
brain compared to ApoE 33 (Vitek et al. 2009).
The failure of NSAIDs in clinical studies with AD
patients may be related to the inhibitory effects on
microglia. One of the physiologic functions of microglial
cells is to clear Ab plaques by phagocytosis as well as
secretion of various proteases (Lee et al. 2010). Evidence
for the role of microglia and their inflammatory mediators
in modulating neurogenesis is also compelling (Ekdahl
et al. 2009). The clearance function declines with age, so
accumulation of plaques continues in spite of increasing
microglial numbers (Hickman et al. 2008). An alternative
explanation for the unfortunate results is that current ani-
mal models of AD reflect early latent phases of disease
rather than progressed disease states (Zahs & Ashe 2010).
If true, NSAID regimens should be initiated during latent
disease phase in predisposed individuals (Cudaback et al.
2014).
Proliferator-activated receptor gamma (PPARc)
agonists
PPARc is expressed in cells of macrophagic lineage and its
activation has anti-inflammatory effects, resulting from
Table 1 Effects of NSAIDs in AD patients
Drug Duration of treatment Dose (mg/day)
Rofecoxib 1 year 25
Naproxen 1 year 440
Rofecoxib 4 years 25
Celecoxib 1 year 400
Ibuprofen 1 year 400
NSAIDs N/A N/A
N/A not applicable
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S. Shadfar et al.
suppression of the production of pro-inflammatory media-
tors (Heneka et al. 2001; Landreth & Heneka 2001). In
addition, PPARc activation is reported to improve mito-
chondrial metabolism and biogenesis (Alaynick 2008).
Ameliorative effects of PPARc agonists on Ab-induced
neuroinflammation and neurotoxicity were first reported in
2000 (Combs et al. 2000), followed by a number of studies
on actions of PPARc agonists in AD animal models
(Mandrekar-Colucci and Landreth 2011) and several clin-
ical trials with PPARc agonists (Nicolakakis &
Hamel 2010; Tobinick & Gross 2008).
The actions of PPARc and its agonists in in vitro and
animal models of AD have been extensively reviewed
(Mandrekar-Colucci & Landreth 2011; Mandrekar-Colucci
et al. 2013; Sodhi et al. 2011). Administration of PPARc
agonists improved cognitive function, suppressed inflam-
mation, and reduced amyloid levels in many mouse models
of AD (Camacho et al. 2004; Combs et al. 2000; Sastre
et al. 2003; Searcy et al. 2012). In a rat AD model, injec-
tion of both ciglitazone and ibuprofen or oral pioglitazone
administration potently suppressed Ab-caused microglial
inflammatory reactions (Heneka et al. 2003). The effects of
pioglitazone and ibuprofen have been investigated in
12-month-old Tg2576 mice and Ab42 levels were only
significantly lowered in ibuprofen-treated animals, but a
trend was observed for pioglitazone (Yan et al. 2003). Oral
treatment with ibuprofen or pioglitazone significantly
reduced microglial activation and neuroinflammatory
markers in 10-month-old APPV717I mice (Heneka et al.
2005b). Interestingly, intraventricular injection of an
antagonist of PPARc, GW9662, increased cerebellar dys-
function and Ab accumulation in APP/PS1 transgenic mice
(Du et al. 2009).
It remains unclear how PPARc agonists ameliorate
cognitive impairment in AD models (Table 2). One pro-
posed mechanism is that the robust anti-inflammatory
effects of PPARc suppress the levels of proinflammatory
cytokines that have been linked to cognitive impairment
(Mandrekar-Colucci & Landreth 2011). Apart from the
anti-inflammatory mechanism, other properties of PPARc
Main effects on cognitive function Reference
Not significant Aisen et al. 2003
Not significant Aisen et al. 2003
Not significant Thal et al. 2005
Not significant Soininen et al. 2007
Not significant Pasqualetti et al. 2009
Worsen in later stage Breitner et al. 2011
Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential…
agonists might be responsible for reversal of the cognitive
deficits. For instance, PPARc agonists are reported to
stimulate Wnt signaling, resulting in neuroprotection in AD
models (Inestrosa & Toledo 2008). Recent works demon-
strated that rosiglitazone-induced activation of ERK path-
way is related to cognitive enhancement of Tg2576 mice
(Denner et al. 2012; Jahrling et al. 2014). In addition,
PPARc agonists improve peripheral insulin sensitivity,
which may enhance cognitive function in AD mice (Craft
et al. 2013).
Cognitive enhancement by PPARc agonists was
demonstrated in several clinical studies. Daily treatment
with 15-30 mg pioglitazone improved cognition and cere-
bral blood flow in mild AD (Sato et al. 2011). In contrast,
no significant therapeutic effects were observed in a ran-
domized pilot clinical trial of the safety of pioglitazone
(Geldmacher et al. 2011). Preliminary data suggested that
rosiglitazone preserved cognition in patients with early AD
and amnestic mild cognitive impairment during treatment
(Watson et al. 2005). Administration of rosiglitazone
(8 mg/day) improved cognitive function only in ApoE
epsilon4 non-carriers, while ApoE epsilon4 allele carriers
showed no improvement or some decline (Risner et al.
2006). However, rosiglitazone failed to show efficacy for
cognition enhancement in AD patients in the largest ran-
domized, double-blind, placebo-controlled trials conducted
to date (Gold et al. 2010). In this study, no beneficial effect
of the drug was detected even in ApoE epsilon4 non-car-
riers. Edema seemed to be a common adverse effect of both
pioglitazone and rosiglitazone in the studies, despite their
generally high tolerability. Although overall results from
clinical trials assessing pioglitazone or rosiglitazone seem
positive for treatment of AD at this moment, pharma-
coepidemiologic studies are warranted before their use can
be recommended for AD treatment (Miller et al. 2011).
Cannabinoids
Cannabinoids exert their physiological effect through two
subtypes of cannabinoid G-protein-coupled receptors (CB1
and CB2). CB1 receptors are abundantly expressed in both
Table 2 Effects of PPARc agonists in AD patients
Drug Duration of Dose (mg/day)
treatment (year)
Pioglitazone 0.5 15–30
Pioglitazone 1.6 45
Rosiglitazone 0.5 4 Preserved cognition
Rosiglitazone 2 2, 4 or 8
Rosiglitazone 2 2 or 8
N/A not applicable
neurons and glial cells and regulate learning and memory,
emotion, motor control, feeding and nociception (Howlett
2005). CB1 receptors are mostly localized in neuron ter-
minals where they modulate excitatory and inhibitory
neurotransmission (Aso & Ferrer 2014). CB2 receptors are
found in the immune system where they are involved in
regulating immune cell migration and cytokine release. In
particular, CB2 receptors are mainly detected in microglial
cells of the nervous system. They inhibit microglia-medi-
ated neurotoxicity, and the main interest in the role of
cannabinoids as anti-inflammatory agents in several dis-
eases involving inflammation has focused on compounds
acting on CB2 receptors (Cabral & Griffin-Thomas 2009).
Abundant evidence indicates that expression of CB2
receptors in microglia surrounding senile plaques is ele-
vated (Solas et al. 2013). Intriguingly, the expression level
correlates with Ab42 levels and plaque deposition, but not
with severity of cognitive impairment, suggesting that
alterations in Ab metabolism induce expression of CB2
receptors.
Agonists of CB2 receptors reduced the neuroinflamma-
tory response to Ab insults in different models of AD (Aso
& Ferrer 2014). Activation of CB2 receptor by the receptor
agonists significantly decreased neuroinflammatory
responses in the brains that received the injection of Ab
(Fakhfouri et al. 2012; Martin-Moreno et al. 2011). Fur-
thermore, similar anti-neuroinflammatory effects by
cannabinoids were observed in APP transgenic and tau-
pathy mice (Aso et al. 2013; Casarejos et al. 2013; Martin-
Moreno et al. 2012). In addition to CB2 receptors, CB1
receptors appeared to downregulate neuroinflammation, as
Aso et al. showed that chronic treatment with the selective
CB1 receptor agonist, arachidonyl-2-chloroethylamide,
reduced the astrocytic expression of the pro-inflammatory
cytokine interferon-c in APP/PS1 transgenic mice (Aso
et al. 2012). Recently, Stumm et al. demonstrated that
deficiency in CB1 receptors exacerbated cognitive impair-
ment in spite of reduced amyloid deposition (Stumm et al.
2013). Cannabidiol, a dual agonist for CB1 and CB2
receptors, also exhibited anti-inflammatory properties in
AD models (Martin-Moreno et al. 2011). These data
Main effects on Reference
cognitive function
Enhancive Sato et al. 2011
Not significant Geldmacher et al. 2011
Watson et al. 2005
Enhancive in subgroup Risner et al. 2006
Not significant Gold et al. 2010
123

suggest that both CB1 and CB2 receptors could attenuate
neuroinflammatory responses in AD models.
The precise mechanisms by which cannabinoids exert
anti-neuroinflammatory and neuroprotective effects remain
to be elucidated. One study indicated that PPARc activa-
tion by cannabidiol is associated with its ameliorative
effects on microglial activation (Esposito et al. 2011). A
cannabinoid derivative attenuated LPS-mediated micro-
glial activation by inhibiting NF-jB signaling pathway
(More et al. 2013). Besides their anti-neuroinflammatory
mechanisms, cannabinoids possess neuroprotective prop-
erties via diminishing excitotoxicity in postsynaptic neu-
rons (Marsicano et al. 2003), enhancing vasodilation
through CB1 in vascular smooth muscle, and the inhibition
of endothelin-1 (Ronco et al. 2007).
A few clinical trials with cannabinoids including dron-
abinol and nabilone showed their effects in AD patients.
Dronabinol treatment decreased severity of altered behav-
ior and increased body weight in AD patients who were
previously refusing food (Volicer et al. 1997). Two studies
described that dronabinol reduced night-time agitation and
behavioral disturbances without adverse effects during the
trial period (Walther et al. 2006; Walther et al. 2011).
Similarly, nabilone reduced the severe agitation and
aggressiveness exhibited by an advanced AD patient who
was refractory to anti-psychotic and anxiolytic medications
(Passmore 2008). However, they did not evaluate cognitive
or neurodegenerative markers in those studies. Importantly,
the revision in 2009 of the Cochrane Dementia and Cog-
nitive Improvement Group Specialized Register found no
evidence of cannabinoid effectiveness in the improvement
of behavior and other parameters of dementia as depicted
in Table 3 (Krishnan et al. 2009). Therefore, these clinical
results suggest that more controlled trials are needed to
assess the effectiveness of cannabinoids in the treatment of
dementia.
Magnolia extract, 4-O-methylhonokiol and obovatol
Magnolia extract contains at least 255 different ingredients
such as 4-O-methylhonokiol and obovatol. Compounds
isolated from Magnolia family have been shown to possess
multiple neuropharmacologic activities (Lee et al. 2011b).
Table 3 Effects of cannabinoid and TNFa antagonist in AD patients
Drug Duration of Dose (mg/day)
treatment
Cannabinoids N/A N/A
Etanercept 0.5 year 25–30
Etanercept Single dose 25
N/A not applicable
123
S. Shadfar et al.
In particular, 4-O-methylhonokiol ameliorated memory
impairment in several different animal models including a
systemic LPS-induced dementia model (Lee et al. 2012a),
presenilin 2 mutant transgenic mice (Lee et al. 2011a), and
Tg2576 mice (Lee et al. 2012b). Obovatol blocked Ab
aggregation and enhanced learning and memory in Tg2576
mice by blocking neuroinflammatory responses and Ab
production (Choi et al. 2012a, b).
Compounds isolated from the Magnolia family seem to
have multiple action mechanisms. Previous studies
revealed that 4-O-methylhonokiol potently inhibited neu-
roinflammatory responses and was associated with cogni-
tive enhancement in AD animal models. The anti-
inflammatory activity was mediated by diminishing NF-jB
signaling pathway (Lee et al. 2012a). Interestingly,
Schuehly et al. demonstrated that 4-O-methylhonokiol acts
like a CB2 receptor ligand (Schuehly et al. 2011). They
suggest that the effects of the compound on CB2 receptors
are associated with anti-neuroinflammatory effects, since
the receptors are primarily associated with a broad range of
inflammatory processes (Gertsch & Anavi-Goffer 2012).
Similar to 4-O-methylhonokiol, Magnolia polyphenols or
obovatol blunted microglial activation in vitro (Chuang
et al. 2013; Ock et al. 2010) and in vivo (Choi et al. 2012b).
No clinical trials with magnolia extract or pure com-
pounds from Magnolia family to assess their therapeutic
effects in AD have been reported to date. Although their
efficacy remains to be tested in AD patients, various studies
demonstrated therapeutic potential as determined by
reduction in pathology and improvement in cognitive
function. Compounds from the Magnolia family such as
4-O-methylhonokiol and obovatol may be strong candi-
dates for intervention in AD.
Agents that inhibit TNFa activity
Increasing evidence indicates that TNFa may play a central
role in the pathogenesis of AD (Trepanier & Milgram
2010). Inhibition of TNFa activity ameliorated AD-like
pathology and cognitive impairment in AD animal models.
Thalidomide, a TNFa inhibitor, significantly attenuated
neuroinflammation, Ab deposition, and tau phosphoryla-
tion (He et al. 2013) and improved memory function
Main effects on Reference
cognitive function
Not significant Krishnan et al. 2009
Enhancive Tobinick et al. 2006
Enhancive Tobinick and Gross 2008
Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential…
(Gabbita et al. 2012). Infliximab, the antibody against
TNFa, reduced the levels of TNFa, amyloid plaques, and
tau phosphorylation in transgenic mice (Shi et al. 2011a).
Interestingly, the same group reported that intrathecal
injection of infliximab enhanced cognitive function in
women with AD, while the antibody increased the con-
centration of Ab1-42 and phospho-tau but not Ab1–40 in the
cerebrospinal fluid and blood 7 days after treatment (Shi
et al. 2011b). Another potent inhibitor of TNFa is etaner-
cept which is currently approved for rheumatoid arthritis.
In a pilot study, perispinal administration of etanercept
(25–50 mg, once weekly) for 6 months significantly
improved all primary efficacy variables relative to baseline
(Tobinick et al. 2006). In addition, the same group reported
significant effects of etanercept on most neuropsychologi-
cal measures and notable improvements in verbal learning,
memory and fluency of 12 patients with mild-to-severe AD
as described in Table 3 (Tobinick & Gross 2008).
Although these small pilot studies show promise for TNF-a
inhibition as a potential therapeutic for AD, these studies
were limited by small sample sizes, open-label design, and
lack of placebo groups. Therefore, a well-designed study
with large scale and placebo group are warranted for
conclusive results of etanercept in AD treatment.
Conclusion
Based on accumulating epidemiological and preclinical data,
the hypothesis has been drawn that inflammatory responses are
highly related to early stage AD. But most clinical trials with
anti-inflammatory agents have not been successful to date and
do not fully support the hypothesis. A number of competing
hypotheses can explain the failure of preclinical studies to
translate into the clinical setting and we cannot presently
confirm which of these explanations is correct. More preclin-
ical studies of the effects of anti-inflammatories on cognition
and the use of more predictive animal models should facilitate
the outcome of true positives detected clinically. The identi-
fication of genetic markers or other biomarkers for the disease
will enable an earlier point of intervention, providing a more
effective means of preventing the inflammatory response. The
development of more selective inhibitors that target specific
mediators in the inflammatory cascade, such as etanercept for
TNF-a, may also offer new therapeutic avenues over nonse-
lective anti-inflammatories.
Acknowledgments This work was fully supported by 2015
Yeungnam University Research Grant.
Compliance with ethical standards
Conflict of interest The authors of the present article declare that
there is no conflict of interest.
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