# PPARs in Alzheimer's Disease

Authors: Markus P. Kummer; Michael T. Heneka
Journal: PPAR Research
 (2008)

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## 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 theβ-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 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, 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.


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## Body

## 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, also
called δ, and PPARγ) have been
identified in all metazoa, 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. Functions of PPARs

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 dominant action is to stimulate adipocyte differentiation and 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 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.PPARs regulate gene expression by
forming heterodimers with retinoid-X-receptors (RXRs). Stimulation of target
gene expression is controlled by specific PPAR-response
elements in the promoter region (PPREs). Under unstimulated conditions, 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 posttranslational modification such as phosphorylation and
sumoylation [5, 6].Like other NHR, PPARs also inhibit
proinflammatory gene expression by a controversial mechanism oftranscriptional 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 transcription
factors [8]. A mechanistic model for the PPARγ-mediated
transrepression has recently been proposed. NFκB-regulated
inflammatory genes are maintained under basal conditions in a repressed state
by N-Cor containing corepressor 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].Binding of PPARs to their specific
ligands leads to conformational changes which allow corepressor release and
coactivator 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 pioglitazone and rosiglitazone which are Food and Drug
Administration (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 efficiencies [11]. An overview addressing the affinity of several natural and synthetic
ligands has recently been summarized [12].


### 1.2. PPARs during Development

PPARα and γ transcripts appear late during fetal
development 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 though PPARγ has been
shown to be present in macrophages in human atheroma.


### 1.3. PPARs in the Brain

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 γdecreases postnatally in the brain [17]. While PPARβ/δ has been
found in neurons of numerous brain areas, PPARα and γhave 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 PPARαis 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
participates in the regulation of lipid metabolism in the brain. This
hypothesis is further supported by the observation that PPARβ/δ 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 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]. The localization of PPARs has also been investigated 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]. PPARα has been suggested to be involved in the
acetylcholine metabolism [31] and to be related to excitatory amino acid neurotransmission and
oxidative stress defence [18].


## 1.1. Functions of PPARs

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 dominant action is to stimulate adipocyte differentiation and 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 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.PPARs regulate gene expression by
forming heterodimers with retinoid-X-receptors (RXRs). Stimulation of target
gene expression is controlled by specific PPAR-response
elements in the promoter region (PPREs). Under unstimulated conditions, 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 posttranslational modification such as phosphorylation and
sumoylation [5, 6].Like other NHR, PPARs also inhibit
proinflammatory gene expression by a controversial mechanism oftranscriptional 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 transcription
factors [8]. A mechanistic model for the PPARγ-mediated
transrepression has recently been proposed. NFκB-regulated
inflammatory genes are maintained under basal conditions in a repressed state
by N-Cor containing corepressor 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].Binding of PPARs to their specific
ligands leads to conformational changes which allow corepressor release and
coactivator 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 pioglitazone and rosiglitazone which are Food and Drug
Administration (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 efficiencies [11]. An overview addressing the affinity of several natural and synthetic
ligands has recently been summarized [12].


## 1.2. PPARs during Development

PPARα and γ transcripts appear late during fetal
development 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 though PPARγ has been
shown to be present in macrophages in human atheroma.


## 1.3. PPARs in the Brain

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 γdecreases postnatally in the brain [17]. While PPARβ/δ has been
found in neurons of numerous brain areas, PPARα and γhave 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 PPARαis 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
participates in the regulation of lipid metabolism in the brain. This
hypothesis is further supported by the observation that PPARβ/δ 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 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]. The localization of PPARs has also been investigated 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]. PPARα has been suggested to be involved in the
acetylcholine 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 βpeptide (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 increased risk for AD [34]. Another key hallmark of AD brain 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 secretion of inflammatory
cytokines and chemokines including interleukin (IL)-1β, IL-6,
monocyte chemotactic protein-1, (MCP-1), and tumor necrosis factor (TNF)-α [36]. It was posited that activation
of microglia and the concurrentproduction 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).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.


## 3. Effects of PPARγ Agonists on Alzheimer's Disease

PPARγ is expressed in the brain at low levels under physiological conditions. Recently, a detailed
gene expression 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 used drugs are
mainly targeted at symptomatic improvement 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 epidemiological 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 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 immunostimulated
Β-site APP cleaving enzyme (BACE1) expression is silenced by a PPARγ-dependent
regulation of the BACE1 gene promoter [53, 54]. Similarly, oral pioglitazone treatment 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], even so this hypothesis has recently been challenged [58, 59].Additionally, modulation of the Wnt/β-catenin
signalling pathway may also account for some PPARγ-mediated
beneficial effects in AD since recent findings show that PPARγ-mediated
protection of hippocampal neurons against 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 cognition 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 been shown that this polymorphism is associated with
higher risk for Alzheimer's disease in octogenarians even after adjustment for
the ApoE4 allele [74].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
improvement 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 metabolism
and mitochondrial biogenesis genes leading to improved 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 [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 influence the pathology of Alzheimer's disease. Beside the
ameliorating effect of PPARγ agonists on the
inflammatory status of 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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*Source: 403896-2008-07-14.xml*