PPARs in Alzheimer's Disease.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.

Full text

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Hindawi Publishing Corporation
PPAR Research
Volume 2008, Article ID 403896, 8 pages
doi:10.1155/2008/403896
ReviewArticle
PPARs in Alzheimer’s Disease
Markus P. Kummer and Michael T. Heneka
Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Correspondence should be addressed to Markus P. Kummer, markus.kummer@ukb.uni-bonn.de
Received 5 February 2008; Accepted 2 June 2008
Recommended by Michael Racke
Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact,
but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple
sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s disease. The observation that PPARs are able to suppress the
inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that
PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during
the course of Alzheimer’s disease (AD) is triggered by the neurodegeneration and the deposition of the β-amyloid peptide in
extracellularplaques.Nonsteroidalanti-inflammatorydrugs(NSAIDs)havebeenconsideredtodelaytheonsetandreducetherisk
to develop Alzheimer’s disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD
may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular
and animal models. Stimulation of PPARγ receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-
amyloidogenic,andinsulinsensitisingeffectsmayaccountfortheobservedeffects.Severalclinicaltrialsalreadyrevealedpromising
results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.
Copyright © 2008 MarkusP. Kummer and MichaelT. Heneka. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
1.INTRODUCTION
The peroxisome proliferator-activated receptors (PPARs)
belong to the family of nuclear hormone receptors (NHR)
that comprise 48 human ligand-inducible transcription
factors, which activity is regulated by steroids and lipid
metabolites. Three different PPAR genes (PPARα, PPARβ,
alsocalledδ,andPPARγ)havebeenidentifiedinallmetazoa,
that show unique spatiotemporal tissue-dependent patterns
of expression during fetal development in a variety of
cell types deriving form the ecto-, meso- or endoderm
in rodents. Functionally PPARs are involved in adipocyte
differentiation, lipid storage, and glucose homeostasis of the
adipose tissue, brain, placenta, and skin (reviewed in [1]).
1.1. FunctionsofPPARs
PPARs act principally as lipid sensors and regulate the
whole body metabolism in response to dietary lipid intake
and direct their subsequent metabolism and storage [2].
The prototypic member of the family, PPARα, was initially
reported to be induced by peroxisome proliferators, and
now denotes the subfamily of three related receptors. The
natural ligands of these receptors are dietary lipids and
their metabolites. The specific ligands have been difficult to
establish, owing to the relatively low affinity interactions and
broad ligand specificity of the receptors.
PPARα acts primarily to regulate energy homoeostasis
through its ability to stimulate the breakdown of fatty
acids and cholesterol, driving gluconeogenesis and reduction
in serum triglyceride levels. This receptor acts as a lipid
sensor, binding fatty acids and initiating their subsequent
metabolism. PPARγ binds a number of lipids including
fatty acids, eicosanoids, and other natural lipid ligands. Its
dominantactionistostimulateadipocytedifferentiationand
to direct lipid metabolites to be deposited in this tissue.
PPARγ operates at the critical metabolic intersection of lipid
and carbohydrate metabolism. PPARγ activation is linked
to reduction in serum glucose levels, likely as a secondary
effect of its ability to regulate endocrine factors. It is this
latter activity that has led to the development of specific
PPARγ agonists for the treatment of type II diabetes [3]. The

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2 PPAR Research
PPARβ/δ binds and responds to VLDL-derived fatty acids,
eicosanoids including prostaglandin A1 [4] and appears to
be primarily involved in fatty acid oxidation, particularly in
muscle.
PPARsregulategeneexpressionbyformingheterodimers
withretinoid-X-receptors(RXRs).Stimulationoftargetgene
expression is controlled by specific PPAR-response elements
in the promoter region (PPREs). Under unstimulated con-
ditions, these heterodimers are associated with corepressors,
like N-CoR and SMRT, which suppress gene transcription
[1]. Upon ligand binding to the nuclear receptor, the
corepressors are displaced and transcriptional coactivators
are recruited to the receptor. These coactivator receptor
complexes finally induce the formation of a much larger
transcriptional complex which subsequently links the basal
transcriptional apparatus and initiates gene transcription.
In addition, activity of PPARs is also regulated by post-
translational modification such as phosphorylation and
sumoylation [5, 6].
Like other NHR, PPARs also inhibit proinflammatory
gene expression by a controversial mechanism of tran-
scriptional transrepression, which is not mediated by their
binding to PPREs. PPARγ is able to suppress expression
of proinflammatory genes in myeloid lineage cells, such as
microglia and macrophages, and in the vasculature [7], by
suppressing the action of NFκB, AP-1, and STAT1 tran-
scription factors [8]. A mechanistic model for the PPARγ-
mediatedtransrepressionhasrecentlybeenproposed.NFκB-
regulated inflammatory genes are maintained under basal
conditionsinarepressedstatebyN-Corcontainingcorepres-
sor complexes. Upon exposure to proinflammatory stimuli
this complex is dismissed and gene expression is initiated.
This dismissal can be prevented by sumoylated PPARγ:
PPARγ agonist complexes that stabilizes NCor complexes
at the promoters of NFκB-regulated genes, thus preventing
inflammatory gene expression [9, 10].
BindingofPPARstotheirspecificligandsleadstoconfor-
mational changes which allow corepressor release and coac-
tivator recruitment. Even though all PPARs can be attributed
to a common ancestral nuclear receptor, each PPAR isotype
has its own properties with regard to ligand binding.
Synthetic thiazolidinediones (TZDs), which are commonly
prescribed for the treatment of type II diabetes, are selective
PPARγ ligands. Naturally occurring PPARγ ligands include
eicosanoids and the prostaglandin 15d-PGJ2. The best
characterized PPARγ agonists are the TZDs including piogli-
tazone and rosiglitazone which are Food and Drug Adminis-
tration (FDA) approved for treatment of type II diabetes and
troglitazone, which was withdrawn in 2000. PPARα ligands
include fibrates that are commonly used for the treatment of
hypertriglyceridemia and the synthetic agonists WY14,643,
and GW7647. PPARβ/δ agonists include the prostacyclin
PGI2, and synthetic agents including GW0742, GW501516,
and GW7842. All three PPAR isotypes can be activated by
polyunsaturated fatty acids with different affinities and effi-
ciencies [11]. An overview addressing the affinity of several
natural and synthetic ligands has recently been summarized
[12].
1.2. PPARsduringdevelopment
PPARα and γ transcripts appear late during fetal develop-
ment of rat and mouse (day 13.5 of gestation), with similar
expression pattern to their adult distribution. PPARα is
found in the liver, the kidney, the intestine, the heart, the
skeletal muscle, the adrenal gland, and the pancreas. PPARγ
expression is restricted to the brown adipose tissue (day 18.5
of gestation), and to the CNS (day 13.5 to 15.5 of gestation).
Compared to the two other isotypes, PPARβ/δ is expressed
ubiquitously and earlier during fetal development [13]. In
adult rodent organs, the distribution of PPARα is similar to
its fetal pattern of expression.
Not much is known about the expression of the PPARs
during human development [14–16]. PPARα is most highly
expressed in tissues that catabolise fatty acids, such as the
adult liver, heart, kidney, large intestine, and skeletal muscle.
PPARβ/δ mRNA is present ubiquitously, with a higher
expression in the digestive tract and the placenta. PPARγ
is abundantly expressed in the white adipose tissue, and is
present at lower levels in the skeletal muscle, the heart, and
the liver. Surprisingly, and in contrast to rodents, human
PPARγ seems to be absent from lymphoid tissues, even
thoughPPARγ hasbeenshowntobepresentinmacrophages
in human atheroma.
1.3.PPARsinthebrain
All three PPAR isotypes are coexpressed in the nervous
system during late rat embryogenesis, and PPARβ/δ is the
prevalent isotype. The expression of the three PPAR isotypes
peaks in the rat CNS between day 13.5. and 18.5 of gestation.
Whereas PPARβ/δ remains highly expressed in this tissue,
the expression of PPARα and γ decreases postnatally in the
brain [17]. While PPARβ/δ has been found in neurons of
numerous brain areas, PPARα and γ have been localized
to more restricted brain areas [18, 19]. Analysis of the
expression of PPARs in different brain regions of adult mice
revealed that PPARβ/δ mRNAs are preferentially found in
the cerebellum, the brain stem, and the cortex, whereas
PPARγ mRNAs are enriched in the olfactory areas as well
as in the cortex. Expression of all three isotypes was found
to be low to moderate in the hippocampus. More detailed
analysis of PPARs expression within the hippocampus by in
situ hybridisation revealed a ubiquitous expression pattern
for PPARα, whereas PPARβ was found to be enriched in
the dentate gyrus/CA1 region and PPARγ expression was
restricted to the CA3 region [20].
Even though this pattern of expression, which is isotype
specific and regulated during development, suggests that the
PPARs may play a role during the formation of the CNS,
their function in this tissue are still poorly understood. Both
in vitro and in vivo observations show that PPARβ/δ is the
prevalent isoform in the brain, and is found in all cell types,
whereas PPARα is expressed at very low levels predominantly
in astrocytes [21]. Acyl-CoA synthetase 2, which is crucial
in fatty acid utilization, is regulated by PPARβ/δ at the
transcriptional level, providing a facile measure of PPARβ/δ
action. This observation strongly suggests that PPARβ/δ

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MarkusP. Kummer and MichaelT. Heneka3
participates in the regulation of lipid metabolism in the
brain. This hypothesis is further supported by the observa-
tionthatPPARβ/δ nullmiceexhibitanalteredmyelinationof
the corpus callosum. Such a defect was not observed in other
regions of the central nervous system, and the expression
of mRNA encoding proteins involved in the myelination
process remained unchanged in the brain.
Expression of all PPAR isoforms, including PPARγ,
has been confirmed in the adult brain. Furthermore, it
has been suggested that PPAR activation in neurons may
directly influence neuron cell viability and differentiation
[22–26].ThelocalizationofPPARshasalsobeeninvestigated
in purified cultures of neural cells. PPARβ/δ is expressed
in immature oligodendrocytes and its activation promotes
differentiation, myelin maturation, and turnover [27, 28].
The PPARγ is the dominant isoform in microglia. Astrocytes
possess all three PPAR isotypes, although to different degrees
depending on the brain area and animal age [29, 30]. The
role of PPARs in the CNS is mainly been related to lipid
metabolism, however, these receptors, especially PPARγ,
have been implicated in neural cell differentiation and death
as well as in inflammation and neurodegeneration [23].
PPARαhasbeensuggestedtobeinvolvedintheacetylcholine
metabolism [31] and to be related to excitatory amino acid
neurotransmission and oxidative stress defence [18].
2. INFLAMMATION AND ALZHEIMER’S DISEASE
The number of individuals with the Alzheimer’s disease
(AD) is dramatically increasing throughout the developed
world. The large number of affected individuals and the
increasing prevalence of the disease presents a substantial
challenge to health care systems and does so in the face of
substantial economic costs. The pathological hallmarks of
AD are the formation of extracellular plaques consisting of
amyloid-β peptides and intracellular neurofibrillary tangles
made up from hyperphosphorylated tau protein, causing
neuronal death that is responsible for progressive memory
loss and inexorable decline of cognitive functions [32, 33].
Analysis of the genetic forms and animal models suggested
a pivotal role for the amyloid β peptide (Aβ), nevertheless,
the biological basis of AD, especially of the sporadic forms,
is still poorly understood. Genetically, Aβ metabolism is
closely linked to lipid metabolism as a certain allele of the
lipid carrier protein ApoE is associated with significantly
increasedriskforAD[34].AnotherkeyhallmarkofADbrain
is the presence of chronic neuroinflammation without any
signs of leukocyte infiltration. Amyloid plaques within the
brain are populated by abundant, activated microglia, and
astrocytes [35]. Microglial activation is accompanied by the
secretionofinflammatorycytokinesandchemokinesinclud-
inginterleukin(IL)-1β,IL-6,monocytechemotacticprotein-
1, (MCP-1), and tumor necrosis factor (TNF)-α [36]. It
was posited that activation of microglia and the concurrent
production of inflammatory molecules may deteriorate and
accelerate the progression of AD and therefore the neuronal
loss [35]. Neuronal expression of inflammatory enzyme
systems, including iNOS, has also been described in AD [37–
39]. Altogether, these data suggest that anti-inflammatory
therapies may be beneficial for AD treatment (see Figure 1).
3.EFFECTS OF PPARγ AGONISTS ON
ALZHEIMER’S DISEASE
PPARγ is expressed in the brain at the low levels under
physiologicalconditions.Recently,adetailedgeneexpression
analysis has demonstrated that mRNA levels are elevated
in AD patients [40]. This suggests that PPARγ plays a role
in the modulation of the pathophysiology of AD. Currently
useddrugsaremainlytargetedatsymptomaticimprovement
of the patients. These agents have only modest therapeutic
efficacy over rather short periods. Thus, the development of
new therapeutic approaches is of critical importance.
The initial studies exploring the actions of PPARγ in AD
were based on the ability of nonsteroidal anti-inflammatory
drugs (NSAID) to activate this receptor. A number of
epidemiologicalstudiesdemonstratedthatNSAIDtreatment
reduces AD risk by as much as 80% and it was suggested that
these effects arise from the ability of these drugs to stimulate
PPARγ and to inhibit inflammatory responses in the AD
brain [41–45]. This hypothesis is supported by the finding
that experimental expression of iNOS in neurons resulted
in time-dependent neuronal cell death which was prevented
by activation of PPARγ in vitro and in vivo [23, 46]. In
addition, PPARγ activation in microglial cells suppressed
inflammatory cytokine expression, iNOS expression, and
NO production as well as inhibited COX2 and therefore
the generation of prostanoids [47]. These latter effects result
from the ability of PPARγ to suppress proinflammatory
genes through antagonism of the transcription factor NFκB,
(and to a lesser extent, AP-1 and STATs) [8]. PPARγ
agonists have also been demonstrated to suppress the Aβ-
mediated activation of microglia in vitro and prevented
cortical or hippocampal neuronal cell death [47–49]. In a
rat model of cortical Aβ injection, coinjection of ciglitazone
and ibuprofen or oral pioglitazone administration potently
suppressed Aβ-evoked microglial cytokine generation. The
effects of the PPARγ agonists pioglitazone and ibuprofen
have been investigated in animal models of AD (Tg2576)
that overexpress human APP. Pioglitazone was selected as
it passes the blood brain barrier, although with limited
penetration [50]. 12 months old Tg2576 mice were treated
orally for 4 months resulting in a significant reduction
of SDS-soluble Aβ40. Aβ42 levels were only significantly
lowered for ibuprofen-treated animals, but a trend was
observed for pioglitazone [51].
The modest effects of pioglitazone in this study were
thought to be due to poor drug penetration into the
brain. In a subsequent study treatment with larger doses of
pioglitazone in aged APPV717I transgenic mice significantly
decreased microglial and astroglial activation as well as Aβ
plaque burden [52]. The finding that PPARγ agonists elicited
a reduction in amyloid pathology may be the result of the
ability of PPARγ to affect Aβ homeostasis. According to this
hypothesis, evidence has been provided that immunostim-
ulated β-site APP cleaving enzyme (BACE1) expression is
silenced by a PPARγ-dependent regulation of the BACE1

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4PPAR Research
Inflammation
NO
Cytokines
Prostaglandins
Secretion of
inflammatory
molecules
Microglia
Astrocyte
Aβ
PPARγ
BACE1 promotor
activity
Activation of
microglia
and astrocytes
Plaque formation
TZDs
NSAIDs
Transcriptional
transrepression
BACE1
Figure 1: Effects of PPARγ on Aβ metabolism. Excessive production or insufficient clearance of Aβ results in its aggregation and finally in
the formation of amyloid plaques. This process induces the activation of microglia as well as astrocytes which respond with the secretion of
proinflammatory molecules like NO, cytokines, and prostaglandins developing the inflammatory phenotype of AD. In addition, cytokines
are able to increase BACE1 activity thereby stimulating Aβ production. PPARγ agonists are able to abate both effects by either transrepress
the production of proinflammatory molecules or directly interfere with the binding of PPARγ to a PPRE in the BACE1 gene promoter.
gene promoter [53, 54]. Similarly, oral pioglitazone treat-
ment of APP transgenic mice reduced BACE1 transcription
and expression. A recent study has found that PPARγ is
associated with enhanced Aβ clearance. PPARγ activation,
in both glia and neurons, led to a rapid and robust uptake
and clearance of Aβ from the medium [55]. It has also been
suggested that NSAIDs act directly on Aβ processing by the
γ-secretase complex resulting in selective decrease of Aβ42
production[56,57],evensothishypothesishasrecentlybeen
challenged [58, 59].
Additionally, modulation of the Wnt/β-catenin sig-
nalling pathway may also account for some PPARγ-mediated
beneficial effects in AD since recent findings show that
PPARγ-mediatedprotectionofhippocampalneuronsagainst
Aβ-induced toxicity directly correlates with β-catenin levels,
inhibition of GSK-3β activity, and increased levels of Wnt-
target genes [24, 60]. Furthermore, recent evidence suggests
that PPARγ activation may also provide protection from
excitotoxic stimuli [61] and positively influences neural stem
cell proliferation and differentiation [62], both mechanisms
that could potentially influence the overall salutary effects
observed in models of neurodegenerative disease.
In a further animal study, Pedersen and colleagues have
demonstrated that rosiglitazone treatment of Tg2576 mice
resulted in behavioural improvement in these animals as
well as in reduction of Aβ42 in the brain. Treatment with
rosiglitazone for 34 months enhanced spatial working and
reference memory [63]. Significantly, drug treatment was
associated with a 25% reduction in Aβ1-42 levels, however
Aβ1-40 levels remained unchanged. This reduction of Aβ1-
42 was argued to arise from increased levels of insulin
degrading enzyme (IDE) in rosiglitazone-treated transgenic
mice, even so IDE has not been reported to be regulated
by PPARγ. IDE is an Aβ degrading metalloprotease that has
been genetically linked to AD [64].
The outcome of two clinical trials of the PPARγ agonist
rosiglitazone has recently been reported [65, 66]. These
studies reported that rosiglitazone therapy improves cog-
nition in a subset of AD patients. Rosiglitazone does not
pass the blood-brain barrier [65, 66], and this has been a
confound in interpreting the CNS actions resulting from
the administration of this drug. These data were interpreted
as evidence for a significant role for peripheral insulin
sensitivity in cognition. AD risk and memory impairment
is associated with hyperinsulinemia, and insulin resistance,
features which characterize type II diabetes [65, 67]. Indeed,
type II diabetes is associated with increased risk of AD
[67, 68]. Indeed, in a replication study PPARγ was found
to be significantly associated with Alzheimer’s disease [69].
Likewise, the Pro12Ala polymorphism within the exon 2
of PPARγ has been already linked to type 2 diabetes,
insulin sensitivity, obesity, and cardiovascular diseases (for
review see [70]). Even so the effect of this polymorphism
is heterogeneous, since the Pro12Ala variant is associated
with a reduced risk for diabetes [71–73], it has recently
beenshownthatthispolymorphismisassociatedwithhigher
risk for Alzheimer’s disease in octogenarians even after
adjustment for the ApoE4 allele [74].

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MarkusP. Kummer and MichaelT. Heneka 5
Clinical investigations of insulin-sensitizing TZDs that
are in clinical use for type II diabetes are currently ongoing.
A small study of 30 patients with mild AD or MCI found
that 6 months of treatment with rosiglitazone resulted in
improved memory and selective attention. A larger trial
of rosiglitazone in AD patients has recently been reported
[75]. More than 500 patients with mild to moderate AD
were treated for 6 months with rosiglitazone, resulting in
a statistically significant improvement in cognition in those
patients that did not possess an ApoE4 allele [65]. Patients
with ApoE4 did not respond to the drug and showed no
improvementinstandardcognitivetests.Asanexplanationit
was suggested that rosiglitazone acts on mitochondria in the
brain,increasingtheirmetabolicefficiencyandnumber.This
hypothesis is supported by the observation that rosiglitazone
induces neuronal mitochondrial DNA expression, enhances
glucose utilization by inducing transcription of glucose
metabolism and mitochondrial biogenesis genes leading to
improved cellularfunction in mice. Noteworthy,these effects
where also observed in animals expressing the ApoE4 allele.
Determination of the amount of rosiglitazone in the brain
revealed that 9–14% of the blood rosiglitazone crossed the
blood brain barrier after oral treatment [76]. The actions
of TZDs on mitochondria occur through both PPARγ-
dependent and independent mechanisms [77]. The basis
of the differential effects of rosiglitazone in individuals
depending on their ApoE genotype is unexplained. The
outcome of this clinical trial is, however, consistent with
previous findings with respect to the influence of the ApoE4
genotype [78–80].
4.CONCLUSION
PPARs exhibit a wide range of activities to positively influ-
ence the pathology of Alzheimer’s disease. Beside the amelio-
ratingeffectofPPARγ agonistsontheinflammatorystatusof
the AD brain by repressing the secretion of proinflammatory
molecules and the enhancement of mitochondrial function,
a direct involvement in the processing of the Aβ peptide
has been demonstrated (Figure 1). The compelling results
from animal models of Alzheimer’s disease underline the
beneficial effects of PPAR agonists for future therapies.
The importance of these activities for the disease altering
actions of PPAR agonist as well as the underlying molecular
mechanisms have to be elucidated in ongoing and future
research.
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