Impact and Therapeutic Potential of PPARs in Alzheimer's Disease.

Abstract

Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including 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 deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal 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 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 by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.

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Current Neuropharmacology, 2011, 9, 643-650
643
1570-159X/11 $58.00+.00 ©2011 Bentham Science Publishers
Impact and Therapeutic Potential of PPARs in Alzheimer's Disease
Michael T. Heneka1,*, Elisabet Reyes-Irisarri 1, Michael Hüll2 and Markus P. Kummer1
1University of Bonn, Department of Neurology, Clinical Neurosciences Unit, Bonn, Germany; 2University of Freiburg,
Department of Psychiatry and Psychotherapy, Freiburg Germany
Abstract: Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism,
but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including
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 deposition of the
?-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal 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 PPAR?. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPAR?.
Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models.
Stimulation of PPAR? by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and
insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results
using PPAR? agonists, therefore PPAR? represents an attractive therapeutic target for the treatment of AD.
Keywords: Neuroinflammation, alzheimer`s disease, PPAR, thiazolidinediones.
INTRODUCTION

belong to the family of nuclear hormone receptors (NHR)
that comprise 48 human ligand-inducible transcription fac-
tors which activity is regulated by steroids and lipid metabo-
lites [reviewed in 1]. Three different PPAR genes (PPAR?,
PPAR?, also called ?, and PPAR?) have been identified in
all metazoa, showing an unique spatio-temporal tissue-
dependent expression pattern during fetal development in a
variety of cell types deriving from the ecto-, meso- or endo-
derm in rodents. Functionally, PPARs are involved in adipo-
cyte differentiation, lipid storage, and glucose homeostasis in
all most all organs including the adipose tissue, brain, pla-
centa and skin [reviewed in 2].
The peroxisome proliferator activated receptors (PPARs)
Functions of PPARs

body metabolism in response to dietary lipid intake and di-
rect their subsequent metabolism and storage [3]. The proto-
typic member of the family, PPAR?, 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.
PPAR? acts primarily to regulate energy homoeostasis
through its ability to stimulate the breakdown of fatty acids
and cholesterol, driving gluconeogenesis and reduction in

*Address correspondence to this author at the University of Bonn, Depart-
ment of Neurology, Clinical Neurosciences, Bonn, Germany;
Tel: +49 228 28713091; Fax: +49 228 287 13166;
E-mail: michael.heneka@ukb.uni-bonn.de
PPARs act principally as lipid sensors and regulate whole

serum triglyceride levels. This receptor acts as a lipid sensor,
binding fatty acids and initiating their subsequent metabo-
lism. PPAR? binds a number of lipids including fatty acids,
eicosanoids and other natural lipid ligands. Its dominant ac-
tion is to stimulate adipocyte differentiation and to direct
lipid metabolites to be deposited in this tissue. PPAR? oper-
ates at the critical metabolic intersection of lipid and carbo-
hydrate metabolism. PPAR? 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 PPAR? agonists
for the treatment of type II diabetes [4]. PPAR?/? binds and
responds to VLDL-derived fatty acids, eicosanoids including
prostaglandin A1 [5] and appears to be primarily involved in
fatty acid oxidation, particularly in the muscle.

mers with retinoid-X-receptors (RXRs). Stimulation of target
gene expression is controlled by specific PPAR-response
elements in the promoter region (PPREs). Under unstimu-
lated conditions these heterodimers are associated with
corepressors, like N-CoR and SMRT, which suppress gene
transcription [2]. Upon ligand binding to the nuclear recep-
tor, the corepressors are displaced and transcriptional coacti-
vators are recruited to the receptor. These coactiva-
tor:receptor complexes finally induce the formation of a
much larger transcriptional complex which subsequently
links the basal transcriptional apparatus and initiates tran-
scription of specific target genes. In addition, activity of
PPARs in general is also regulated by posttranslational
modification such as phosphorylation and sumoylation [6,7].
PPARs regulate gene expression by forming heterodi-

vation. Thus, phosphorylation can negatively or positively
affect PPAR? activity depending on which specific protein
There are several mechanisms involved in PPAR? inacti-

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644 Current Neuropharmacology, 2011, Vol. 9, No. 4
Heneka et al.
residue is modified. It has been shown that S82 (for
PPAR?1) /S112 (PPAR?2) phosphorylation, by ERK and
JNK pathways result in PPAR? inhibition [8-11]. If this ser-
ine is substituted by alanine (S82A in mice, or S84A in hu-
man), MAPK mediated PPAR? inhibition is lost [8,12].
Studies introducing a serine to aspartate (S112D) mutation
suggest that the mechanism by which the N-terminus modu-
lates ligand binding is caused by conformational changes of
the unligated receptor and that the S112 phosphorylation
status influences its conformation thereby decreasing its af-
finity for the ligand [9]. Serine (S82/S112) phosphorylation
affects not only coactivators and co-repressors recruitment
but also ubiquitination, proteasomal degradation and sumoy-
lation [13]. For example PPAR? activity is decreased via the
ubiquitination degradation pathway [14]. Alternatively,
PPAR? sumoylation, which is enhanced by S112 phosphory-
lation, promotes the co-repressors recruitment and the re-
pression of inflammatory or adipocyte differentiation genes
[6,15]. In addition, SUMO-1 also affects PPAR? stability but
not the nuclear localization of PPAR? [16]. One S82/S112
independent mechanism that affects the genomic actions of
PPAR? is its translocation to the cytoplasm by the AF-
2/PPAR?/MEKs-interaction after a mitogenic stimulus or
PPAR? ligand administration [17]. On the other hand the
PPAR? translocation to the nucleus induced by the ligand
binding is blocked upon nitration of tyrosine residues [18].

gene expression by a controversial mechanism of transcrip-
tional transrepression, which is not mediated by their bind-
ing to PPREs. PPAR? is able to suppress expression of
proinflammatory genes in myeloid lineage cells, such as mi-
croglia and macrophages, and in the vasculature, by sup-
pressing the action of other transcription factors like NF?B,
AP-1 and STAT1 [19]. One mechanistic model, the corep-
ressor-dependent transrepression, has recently been pro-
posed: under basal conditions NF?B-regulated inflammatory
genes are maintained in a repressed state by N-Cor contain-
ing corepressor complexes. Upon exposure to proinflamma-
tory stimuli this N-Cor containing complex is dismissed and
gene expression is initiated. This dismissal can be prevented
by sumoylated PPAR?:PPAR? agonist complexes that stabi-
lizes NCor complexes at the promoters of NF?B-regulated
genes, thus preventing inflammatory gene expression
[20,21].
Like other NHR, PPARs also inhibit proinflammatory

formational changes which allow co-repressor release and
co-activator recruitment. Even though all PPARs can be at-
tributed 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
PPAR? ligands. Naturally occurring PPAR? ligands include
eicosanoids and the prostaglandin 15d-PGJ2. The best char-
acterized PPAR? agonists are pioglitazone and rosiglitazone
which are Food and Drug Administration (FDA) approved
for treatment of type II diabetes and troglitazone, which has
been withdrawn in 2000. PPAR? agonistic ligands include
fibrates that are commonly used for the treatment of hyper-
triglyceridemia and WY14,643 and GW7647. PPAR?/? ago-
nists include the prostacyclin PGI2, and synthetic com-
Binding of PPARs to their specific ligands leads to con-
pounds GW0742, GW501516, and GW7842. In addition, all
PPARs can be activated by polyunsaturated fatty acids with
different affinities [22]. An overview addressing the affinity
of several natural and synthetic ligands has recently been
summarized [23].
PPARs During Development

opment of rat and mouse (day 13.5 of gestation), with similar
expression pattern to their adult distribution. PPAR? is
found in the liver, the kidney, the intestine, the heart, the
skeletal muscle, the adrenal gland and the pancreas. PPAR?
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, PPAR?/? is expressed
ubiquitously and earlier during fetal development [24]. In
adult rodent organs, the distribution of PPAR? is similar to
its fetal pattern of expression.
PPAR? and ? transcripts appear late during fetal devel-

during human development [25-27]. PPAR? is most highly
expressed in tissues that catabolise fatty acids, such as the
adult liver, heart, kidney, large intestine and skeletal muscle.
PPAR?/? mRNA is present ubiquitously, with a higher ex-
pression in the digestive tract and the placenta. PPAR? is
abundantly expressed in the white adipose tissue, and is pre-
sent at lower levels in the skeletal muscle, the heart and the
liver. Surprisingly, and in contrast to rodents, human PPAR?
seems to be absent from lymphoid tissues, even though
PPAR? has been shown to be present in macrophages in hu-
man atheroma.
Not much is known about the expression of the PPARs
PPARs in the Brain

system during late rat embryogenesis, and PPAR?/? is the
prevalent isotype. The expression of the three PPAR isotypes
peaks in the rat CNS between day 13.5. and 18.5 of gesta-
tion. Whereas PPAR?/? remains highly expressed in this
tissue, the expression of PPAR? and ? decreases postnatally
in the brain [28]. While PPAR?/? has been found in neurons
of several brain areas, PPAR? and ? have been localized to
more restricted brain regions [29,30]. Analysis of the expres-
sion of PPARs in different brain regions of adult mice re-
vealed that PPAR?/? mRNAs are preferentially found in the
cerebellum, the brain stem and the cortex, whereas PPAR?
mRNAs are enriched in the olfactory bulb 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 hy-
bridisation revealed an ubiquitous expression pattern for
PPAR?, whereas PPAR?/? was found to be enriched in the
dentate gyrus/CA1 region and PPAR? expression was re-
stricted to the CA3 region [31].
All three PPAR isotypes are co-expressed in the nervous

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 PPAR?/? is the
prevalent isoform in the brain, and is found in all cell types,
whereas PPAR? is expressed at very low levels predomi-
nantly in astrocytes [32]. Acyl-CoA synthetase 2, which is
Even though this pattern of expression, which is isotype

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Impact and Therapeutic Potential of PPARs in Alzheimer's Disease Current Neuropharmacology, 2011, Vol. 9, No. 4 645
crucial in fatty acid utilization, is regulated by PPAR?/? at
the transcriptional level, providing a facile measure of
PPAR?/? action. This observation strongly suggests that
PPAR?/? participates in the regulation of lipid metabolism in
the brain. This hypothesis is further supported by the obser-
vation that PPAR?/? null mice exhibit an altered myelination
of the corpus callosum. Such a defect was not observed in
other regions of the central nervous system, and the expres-
sion of mRNA encoding proteins involved in the myelination
process remained unchanged in the brain.

been confirmed in the adult brain. Furthermore, it has been
suggested that PPAR activation in neurons may directly in-
fluence neuron cell viability and differentiation [33-37]. Of
note, selective knockdown of PPAR? renders neurons more
vulnerable to oxygen-glucose deprivation in vitro as well as
to ischemic brain damage in vivo [38]. Furthermore, neu-
ronal PPAR? seems to have, at least in vitro, an important
function for neurite outgrowth [39].
Expression of all PPAR isoforms, including PPAR?, has

purified cultures of neural cells. PPAR?/? is expressed in
immature oligodendrocytes and its activation promotes dif-
ferentiation, myelin maturation and turnover [40,41]. The
PPAR? is the dominant isoform in microglia. Astrocytes
possess all three PPAR isotypes, although to different de-
grees depending on the brain area and animal age [42,43].
The role of PPARs in the CNS is mainly been related to lipid
metabolism, however, these receptors, especially PPAR?,
have been implicated in neural cell differentiation and death
as well as in inflammation and neurodegeneration [34].
PPAR? has been suggested to be involved in the acetylcho-
line metabolism [44] and to be related to excitatory amino
acid neurotransmission and oxidative stress defence [29].
The localization of PPARs has also been investigated in
Inflammation and Alzheimer’s Disease

(AD) is dramatically increasing as a consequence of a longer
life expectancy in our societies. The large number of affected
individuals and the increasing prevalence of the AD 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-? peptides and intracellular neurofi-
brillary tangles made up from hyperphosphorylated tau pro-
tein, causing neuronal death that is responsible for progres-
sive memory loss and inexorable decline of cognitive func-
tions [45,46]. Analysis of the genetic forms and animal mod-
els suggested a pivotal role for the amyloid ? peptide (A?),
nevertheless, the biological basis of AD, especially of the
sporadic forms, is still poorly understood. Genetically, A?
metabolism is closely linked to lipid metabolism as a certain
allele of the lipid carrier protein ApoE is associated with
significantly increased risk for AD [47]. Another key hall-
mark of AD brain is the presence of chronic neuroinflamma-
tion without any signs of leukocyte infiltration. Amyloid
plaques within the brain are populated by abundant, activated
microglia and astrocytes [48]. Microglial activation is ac-
companied by the secretion of inflammatory cytokines and
chemokines including interleukin (IL)-1?, IL-6, monocyte
chemotactic protein-1, (MCP-1) and tumor necrosis factor
The number of individuals with the Alzheimer’s disease
(TNF)-? [49]. It was postulated that activation of microglia
and the concurrent production of inflammatory molecules
may deteriorate and accelerate the progression of AD and
therefore directly contribute to neuronal loss [48,50]. Next to
microglia, activation of astrocytes and glial derived inflam-
matory molecules may as well as neuronal expression of
inflammatory enzyme systems, including iNOS, in signifi-
cantly contribute the inflammatory component of AD [51-
53]. Increasing evidence suggests that anti-inflammatory
therapies may be beneficial for AD treatment see Fig. (1).
PPAR? ? in Experimental Models of Alzheimer’s Disease
PPAR? is expressed in the brain at low levels under
physiological conditions. Recently, a detailed gene expres-
sion analysis has demonstrated that mRNA levels are ele-
vated in AD patients [54]. This suggests that PPAR? ?could
play a role in the modulation of the pathophysiology of AD.
Currently used drugs are mainly targeted at symptomatic
improvement of the patients. These agents have only modest
therapeutic efficacy over rather short periods of time. Thus,
the development of new therapeutic approaches is of critical
importance.

were based on the ability of non-steroidal anti-inflammatory
drugs (NSAID) to activate this receptor. A number of epi-
demiological studies demonstrated that NSAID treatment
reduces AD risk by as much as 80% and it was suggested
that these effects arise from the ability of these drugs to
stimulate PPAR? and to inhibit inflammatory responses in
the AD brain [55-59]. 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 PPAR? in vitro and in vivo
[34,60]. In addition, PPAR? activation in microglial cells
suppressed inflammatory cytokine expression, iNOS expres-
sion and NO production as well as inhibited COX2 and
therefore the generation of prostanoids [61]. These latter
effects result from the ability of PPAR? to suppress proin-
flammatory genes through antagonism of the transcription
factor NF?B, (and to a lesser extent, AP-1 and STATs) [19].
PPAR? agonists have also been demonstrated to suppress the
A?-mediated activation of microglia in vitro and prevented
cortical or hippocampal neuronal cell death [61-63]. In a rat
model of cortical A? injection, coinjection of ciglitazone and
ibuprofen or oral pioglitazone administration potently sup-
pressed A?-evoked microglial cytokine generation [64]. The
effects of the PPAR? 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 penetra-
tion [65]. 12 months old Tg2576 mice were treated orally for
4 months resulting in a significant reduction of SDS-soluble
A?40. A?42 levels were only significantly lowered for ibu-
profen treated animals, but a trend was observed for pioglita-
zone, too [66].
The initial studies exploring the actions of PPAR? in AD

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 A? plaque
The modest effects of pioglitazone in this study were

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646 Current Neuropharmacology, 2011, Vol. 9, No. 4
Heneka et al.
burden [67]. The finding that PPAR? agonists elicited a re-
duction in amyloid pathology may be the result of the ability
of PPAR? to affect A? homeostasis. According to this hy-
pothesis, evidence has been provided hat immunostimulated
beta secretase 1 (BACE1) expression is silenced by a
PPAR?-dependent regulation of the BACE 1 gene promoter
[68,69]. Similarly, oral pioglitazone treatment of APP trans-
genic mice reduced BACE1 transcription and expression. A
recent study has found that PPAR? is associated with en-
hanced A? clearance. PPAR? activation, in both glia and
neurons, led to a rapid and robust uptake and clearance of
A? from the medium [70]. It has also been suggested that
NSAIDs act directly on A? processing by the ?-secretase
complex resulting in selective decrease of A?1-42 produc-
tion [71,72], even so this hypothesis has recently been chal-
lenged [73,74].
Additionally, modulation of the Wnt/?-catenin signalling
pathway may also account for some PPAR? mediated bene-
ficial effects in AD since recent findings show that PPAR?
mediated protection of hippocampal neurons against A?-
induced toxicity directly correlates with ?-catenin levels,
inhibition of GSK 3? activity and increased levels of Wnt-
target genes [35,75]. Furthermore, recent evidence suggests
that PPAR? activation may also provide protection from ex-
citotoxic stimuli [76] and positively influences neural stem
cell proliferation and differentiation [77], both mechanisms
that could potentially influence the overall salutary effects
observed in models of neurodegenerative disease.


demonstrated that rosiglitazone treatment of Tg2576 mice
resulted in behavioural improvement in these animals as well
In a further animal study, Pedersen and colleagues have
as in reduction of A?1-42 in the brain. Treatment with
rosiglitazone for 7 months enhanced spatial working and
reference memory [78]. Significantly, drug treatment was
associated with a 25 % reduction in A?1-42 levels, however
A?1-40 levels remained unchanged. Similar results were
obtained in a recently published study in 10 month of J20
mice, treated with rosiglitazone for 4 weeks [79]. This reduc-
tion of A?1-42 was argued to arise from increased levels of
insulin degrading enzyme (IDE) in rosiglitazone treated
transgenic mice. In line with this, it has been suggested that
IDE is positively regulated by PPAR? in primary neurons
[80]. IDE is a A? degrading metalloprotease, that has been
genetically linked to AD [81]. Similarly, chronic treatment
of hAPP mice with rosiglitazone reverted memory decline
and hippocampal glucocorticoid receptor down-regulation
[81]. In addition, prevention of cognitive decline in an in-
tracerebroventricular infusion model of A?1-40 by telmisar-
tan, a partial PPAR? agonist, was abolished when mice were
treated with the PPAR? antagonist GW9662, further support-
ing a role of PPAR? for neuroprotection [82]. Interestingly,
infusion of the same drug into the fourth ventricle of
APPPS1 transgenic mice increased A? levels and gliosis
within the cerebellum, Consequently, these mice did show a
reduction of IDE expression and impaired motor function
[83].
PPAR? ? and Alzheimer`s Disease

all risk of Alzheimer`s disease have almost only be ad-
dressed for the PPAR?2Pro12Ala polymorphism, albeit a
change in PPAR? activity by this mutation will most likely
affect the adipose tissue. However, a recent study revealed a
The influence of genetic mutations on the course or over-












Fig. (1). Effects of PPAR? on A? metabolism. Excessive production or insufficient clearance of A? 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 A? production. PPAR? agonists are able to abate both effects by either transrepress the
production of proinflammatory molecules or directly interfere with the binding of PPAR? ?to a PPRE in the BACE1 gene promoter.
cytokines
Aβ
BACE1
PPARγ
BACE1 promoter
activity
secretion
of inflammatory
molecules
activation
of microglia
and astrocytes
plaque
formation
inflammation
prostaglandins
NSAIDs
TZDs
transcriptional
transrepression
NO
astrocyte
microglia

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Impact and Therapeutic Potential of PPARs in Alzheimer's Disease Current Neuropharmacology, 2011, Vol. 9, No. 4 647
significant overrepresentation of the Ala12 allele in octoge-
narian AD patients [84], suggesting that carrying this poly-
morphism increased the AD risk in this population by nearly
twofold. In contrast to the above, another study showed that
the Ala12 polymorphism protected from AD in females but
not in males [85]. Two further studies, investigating a Ger-
man and a Finnish population failed to detect any significant
association between the Ala 12 variant and the genetic risk
of AD [86,87]. However, the study by Koivisto and col-
leagues, who analyzed the Pro12Ala as well as the C478T
polymorphisms suggests that the carriers of both alleles have
a lower age of onset compared to Pro12Pro/478CC carriers
[86]. Importantly, this effect was independent of the ApoE4
status and various other factors. This finding has been partly
reproduced in a recent study of a Chinese population, that
found that in a subgroup of ApoE4 non-carriers, the
Pro12Ala polymorphism was associated with an earlier dis-
ease onset [88]. In diabetics, however, Ala12 allele carriers
show an increased risk of dementia or cognitive impairment
in general when compared to non-carriers [89,90]. Exceeding
these previous studies and looking at further single nucleo-
tide polymorphisms (SNPs) in the PPAR? gene, Helisalmi
and colleagues failed to find any association between AD
and their study groups in a Finnish population [91]. There-
fore, a strong influence of PPAR? gene polymorphisms on
AD risk seems to be rather unlikely. Conducting a more de-
tailed SNP-analysis may settle this contradiction. However,
it may be important to gain deeper mechanistic understand-
ing of the Pro12Ala mutations in peripheral tissues, thereby
potentially revealing further insight on the interplay of obe-
sity, insulin sensitivity and cholesterol metabolism in the
context of AD.

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 im-
proved memory and selective attention. A larger trial of
rosiglitazone in AD patients has recently been reported [92].
More than 500 patients with mild to moderate AD were
treated for 6 months with rosiglitazone, resulting in a statisti-
cally significant improvement in cognition in those patients
that did not possess an ApoE4 allele [93]. Patients with
ApoE4 did not respond to the drug and showed no improve-
ment in standard cognitive tests. As an explanation it was
suggested that rosiglitazone acts on mitochondria in the
brain, increasing their metabolic efficiency and number. This
hypothesis is supported by the observation that rosiglitazone
induces neuronal mitochondrial DNA expression, enhances
glucose utilization by inducing transcription of glucose me-
tabolism and mitochondrial biogenesis genes leading to im-
proved cellular function 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 [94]. The actions of
TZDs on mitochondria occur through both PPAR? dependent
and independent mechanisms [95]. The basis of the differen-
tial 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 [96-98]. A
Clinical investigations of insulin-sensitizing TZDs that
recently published single center clinical trial using pioglita-
zone for the first time in type II diabetic AD patients showed
a significant improvement concerning neuropsychological
tests, regional cerebral blood flow as well as plasma A?
levels in response to pioglitazone treatment. In strong
contrast, most of these parameters worsened in the control
population without pioglitazone treatment [99]. While this
study is limited by its small number of recruited patients and
an open- but not placebo controlled trial design, it strongly
calls for a more elaborated study.
CONCLUSION

influence the pathology of Alzheimer’s disease. Beside the
ameliorating effect of PPAR? agonists on the inflammatory
status of the AD brain by repressing the secretion of proin-
flammatory molecules and the enhancement of mitochon-
drial function, a direct involvement in the processing of the
A? peptide has been demonstrated Fig. (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 future research.
PPARs exhibit a wide range of activities to positively
ABBREVIATIONS
A? = Amyloid ?
AD = Alzheimer`s disease
BACE =
?-secretase
IDE = Insulin degrading enzyme
IL = Interleukin
MCI = Mild cognitive impairment
NF?B = Nuclear factor ?B
NSAID = Non steroidal anti-inflammatory drug
PPAR = Peroxisome proliferator activated receptor
SNP = Single nucleotide polymorphism
TNF?
TZD
= Tumor necrosis factor-?
Thiazolidinedione =
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Received: April 10, 2010

Revised: February 07, 2011 Accepted: March 14, 2011