# Peroxisome Proliferator-Activated Receptorβ/δ in the Brain: Facts and Hypothesis

Authors: M. G. Hall; Laure Quignodon; Béatrice Desvergne
Journal: PPAR Research
 (2008)

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## Abstract

peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARβ action in the central nervous system remains sketchy. The lipid content alteration observed in PPARβ null brains and the positive action of PPARβ agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARβ acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARβ could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARβ agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARβ in the brain. This review proposes different leads for future researches.


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## Body

## 1. Introduction

Nuclear  receptors (NRs) represent the largest
family of transcription  factors  [1]. Up to today, 48 nuclear receptors have been
described in humans and 49 in mice
[2]. Most of them are ligand-dependent receptors; their
specific ligands correspond to a diversity of hormones, steroids, fat-soluble
vitamins, fatty acids, oxysterols, bile acids, and dietary lipids [3]. This broad range of ligand diversity and
capacity to regulate gene expression makes the NRs key regulators of many
pathways involved in reproduction, metabolism, and development. The central
nervous system (CNS) expresses nearly all the NRs [2], but for most of them we are still missing
in-depth knowledge of their role in brain development, cognition, behavior, and
neurological or psychiatric disorders [4]. Among the NR superfamily, the peroxisome
proliferator-activated receptors (PPARs), which are described as lipid sensors,
are the focus of intense interest, particularly in the context of metabolic
disorders and the associated search for new therapies. Amazingly, in addition
to its metabolic activity in peripheral organs [5], the PPAR beta/delta isotype is highly expressed
in the brain [6] and its deletion in mice is associated with a
brain developmental defect [7].In vertebrates,
the PPAR family is composed of three different isotypes. They are known as
PPARα (NR1C1), PPARβ (NR1C2) also named PPARδ , and PPARγ (NR1C3) [8, 9].
PPARs regulate whole body metabolism
in response to dietary lipid intake, by directing their subsequent metabolism
and storage. Among their endogenous ligands are poly-unsaturated fatty acids
and lipid derivatives such as eicosanoids. However, the search for specific
ligands interacting with the three individual receptors of the family has been
difficult, owing to their relatively low affinity interactions and broad ligand
specificity. PPAR: retinoid-X-receptor (RXR) heterodimers represent the
functional entities and bind to conserved regulatory DNA elements and termed peroxisome
proliferator response elements (PPREs). PPREs correspond to a repetition of two
hexamers, derived from the AGGTCA consensus motif, separated by one nucleotide,
and we still understand little on the binding selectivity of the three PPAR
isotypes according to the nucleotide sequence of these response elements.
PPAR-mediated transcriptional activity is a multistep process. In the absence
of ligands, PPAR is associated with corepressors. Upon ligand binding, they are
replaced by coactivators, which recruit the basal transcriptional machinery.
Thus, PPAR transcriptional activity is depending on a combination of ligand
availability, RXR expression, and numerous cofactor interactions. This
complexity together with a relatively specific tissue expression of PPARα and
PPARγ contributes to the selective PPAR isotype activity.PPARβ is an
intriguing member of the PPAR family. It presents a fairly ubiquitous
expression pattern from early embryonic up to adult stages. Its near-ubiquitous
expression raised early speculation that it may have a “general housekeeping
role” [10]. The phenotype of PPARβ-null mice highlights
its role in development. PPARβ deletion induces a high rate of embryonic
mortality around early embryonic day 10.5 (E10.5) due to a placental defect [7, 11, 12]. The phenotype of the surviving PPARβ-null
mice is rather mild. They present a reduction of adipose tissue [7], an altered skin inflammatory response [7, 13], a decreased number of Paneth cells in the
intestine [14], some discrete metabolic modification in
muscle [7, 15], and impaired wound healing [16]. PPARβ-null mice also present a myelin
alteration [7] but exploration of the PPARβ function in the
brain remains sketchy. In this review, we highlight the few known facts and propose
some hypotheses.


## 2. Evidence for PPARβ Activity in the Brain

During development, PPARβ
expression starts at mid-gestation, around E10.5 days in rats, and then reaches
a peak in all neural tissue between E13.5 and E15.5 [17]. Even though it then fades slightly, it
remains high all through development and adult life. In the adult brain, PPARβ
is expressed ubiquitously, with high levels found in the cerebral cortex,
thalamus, cerebellum, and brain stem [4, 18, 19]
(Figure 1).Expression
of PPARβ in the adult mouse brain.
Quantitative and spatial expression of PPARβ in the mouse brain: (a) Quantitative
RT-PCR data, (b) Brain sagittal section. Moderated expression levels are in red
and weak expression in blue. OA: olfactory areas, Cx: cerebral cortex, CP:
caudate putamen, Hi: hippocampus, Th: thalamus, Hy: hypothalamus, Arc: arcuate
nucleus, Co: colliculus, BS: brain stem, Cb: cerebellum. (MousePat:
http://www-mci.u-strasbg.fr/mousepat/-consulted 8-08-2008).
(a)(b)Most brain cell types appear to express PPARβ. Immunostaining, western
blots, and RT-PCR confirmed their expression in primary cultures of embryonic
cortical neurons [20]. Analyses of adult brain sections enabled more
detailed observations [21] revealing that pyramidal cells of the cerebral
cortex, neurons of the hypothalamus, and accumbens nuclei show high PPARβ
expression. In situ hybridization coupled to immunolocalization revealed PPARβ
mRNA and protein expression within the oligodendrocytes of the corpus callosum [19, 22]. PPARβ is also expressed in primary cultures
of rat cortical and cerebral astrocytes, as well as in mouse cortical
astrocytes [23, 24], even if, in vivo, astrocytes appear negative to PPARβ immunostaining, at
least in the hippocampal commissure [19, 22].Thus, the expression of PPARβ is documented in the three main neural
cell types: neurons, astrocytes, and oligodendrocytes, whereas we still have no
information for microglia cells. Interestingly, PPARβ mRNA is also expressed in
the rat brain capillary endothelial cells [25], suggesting that it plays a role in the
brain-blood barrier.Concerning its cellular localization, PPARβ
immunostaining is detected in the cytoplasm and neurites of some neurons [21], raising the question of PPARβ nongenomic
effects in these specific cells. However, its main localization is nuclear, as
revealed by its exclusive detection in the nuclear fraction of whole brain
protein extracts [26].PPARβ expression pattern suggests that it is
involved in basic physiological functions in the brain. However, the brain
phenotype of PPARβ-null mice is poorly documented. In one study, the authors
noted that PPARβ-null mice brain diameters are significantly smaller than in
wild-type mice, most likely due to their relatively smaller body size [7]. Histological examination revealed alterations in the extent of
myelination in the corpus callosum, more often in female than in male mice
(three of five females; two of seven males). This defect is absent in other
parts of the brain, including the cerebellum and brain stem. The two main
proteins playing a role in myelin
organization, myelin basic protein (MBP)
and proteolipid protein (PLP), are not differentially expressed in the
corpus callosum of PPARβ-null mice, despite a putative PPRE in the PLP promoter [27].Thus, the full functional exploration of PPARβ
activity in the brain remains to be performed. In the
following sections, we summarize and comment on studies that chart the first
leads in this domain.


## 3. PPARβ and Lipid Metabolism in the Brain

The best-known role of PPARβ, with possible consequences on the whole
organism, is to increase lipid oxidative metabolism in muscles, in particular
fatty acid peroxisomal-β oxidation [28]. Along this line, long-term treatment of obese
animals with the PPARβ agonist GW501516 causes significant weight loss
accompanied by improvement of the lipoprotein profiles and metabolic parameters [29, 30]. Interestingly, the brain lipid content of
PPARβ-null mice is altered in females: they present a 24% and 17% increase in
plasmenylethanolamine and phosphatidylserine, respectively, and a 9% decrease
in the level of phosphatidylinositol when compared to controls animals [31].
The altered phospholipid composition in female PPARβ-null brains could
result from a defect in brain peroxisomal acyl-CoA utilization. If true, this
could explain the altered myelination observed in PPARβ-null mice, as
inactivation of peroxisomal β oxidation function induces demyelination in human
and mouse brain [32]. The fact that a PPARβ selective agonist
(L165041) increases the expression of AcylCoA synthtase 2 (ASC2) in rat brain
cell cultures [33] supports a direct role of PPARβ on brain lipid
metabolism. ASC2 turns fatty acids into fatty acyl-CoA, a modification required
for their metabolism. However, in unchallenged conditions, ASC2 expression is
not changed in the adult brains of PPARβ-null mice compared to wild-type mice
[7].
If confirmed, the modification of
brain lipid composition in PPARβ-null mice may have multiple impacts, including
a modification of membrane plasticity or an alteration of pathways requiring
lipid post-translational modifications. For example, acylation is a common
post-translational modification of myelin proteins [34] such as PLP, which is crucial for the
stabilization of myelin sheets. Another example is the processing of Shh, which
undergoes cholesterol addition and palmitoylation to contribute to forebrain
patterning [35]. Finally, an alteration of the lipid
metabolism can directly perturb neural differentiation, as discussed above.Numerous recent papers have
highlighted the role of PPARβ in cholesterol metabolism [36–40]. Even though the CNS accounts for only 2.1% of
body weight, it  contains 23% of the sterols
present in the whole body pool. In
PPARβ-null mice, the total cholesterol content of the brain is not changed
compared to that of wild-type mice [31]. Nevertheless, it does not imply that brain
cholesterol metabolism is not impaired. Cholesterol in the CNS comes almost
entirely from in situ synthesis
with little or no transfer from the blood into the brain, whereas cholesterol
can leave the brain and pass into the general circulation in the form of
24-hydroxycholesterol. Inside the brain, a large amount of the cholesterol
turnover is between glial cells and neurons during CNS development, but also
occurs in the context of neuronal repair and remodeling. This internal recycling
involves the cellular exchange of cholesterol through intermediate binding to
apolipoproteins E and A1. Interestingly, alteration of the cholesterol balance
across the whole body may alter sterol recycling and apolipoprotein E
expression within CNS, thereby affecting neuron and myelin integrity [41]. Altogether, these observations are a strong
incitement to exploring whether PPARβ acts on the fatty acids and cholesterol
metabolisms in the brain.


## 4. PPARβ and Neural Cell Fate

In different models, PPARβ has a
prodifferentiation activity, observed for various cell types such astrophoblast giant cells
[12], adipocytes [42, 43], sebocytes, Paneth cells in the intestine [14], and keratinocytes under normal and
inflammatory conditions [13, 44]. There is now some evidence that PPARβ favors
neural cell differentiation (Figure 2). However, observations vary according to
the models investigated and many questions must be further addressed.Figure 2
PPARβ potential
role in neural cell differentiation during development.
PPARβ is expressed in the embryo and in the
differentiating cells of the CNS and plays important role for the maintenance and/or
differentiation of neural stem cells (NSC). PPARβ maintains NSC in an
undifferentiated proliferative status [45]. Once the NSC cells have started to
differentiate, PPARβ could play a role in (1) neuronal differentiation, inducing
the morphological characteristics and the gene expression patterns of neuronal
cells, (2) promoting the
oligodendrocyte precursor cells (OPC) differentiation [46], strongly expressing PPARβ [47], to mature oligodendrocytes [7]. In promoting differentiation, PPARβ also influences
cell cycle and proliferation rate. Up
to today no role has been clearly established for PPARβ in astrocyte differentiation.
(↑ Activation in red, ⊥ Repression in blue).Oligodendrocytes are the myelin-producing
cells in the CNS. The timing of oligodendrocyte differentiation depends on an
intrinsic clock in oligodendrocyte precursor cells (OPC) that counts time or
cell divisions and limits precursor cell proliferation. The timing of
oligodendrocyte differentiation depends on hormonal signals such as thyroid
hormones, glucocorticoids, and retinoic acid, which bind and activate their
cognate nuclear receptor [48]. Two facts suggest a role of PPARβ in OPC
differentiation: first, the strong expression of PPARβ in these cells [47], and second the partial alteration of the
corpus callosum myelination in the brain of PPARβ-null mice [7]. Cell culture experiments support this
hypothesis. In primary glial cell cultures and oligodendrocyte enriched
cultures prepared from neonatal mouse brains, different PPARβ agonists
accelerated OPC differentiation within 24 hours [46]. These treatments induced by two- to
three-fold the number of oligodendrocytes with processes and huge membrane
sheets. They also increased the expression of some differentiation markers,
such as MBP and PLP, at the mRNA and protein levels [46]. While this prodifferentiation activity
remains to be further documented in
vivo, it suggests that PPARβ contributes to the dietary lipid activity
in accelerating myelinogenesis [49, 50].At the present time, we have few
clues for how PPARβ acts on oligodendrocyte differentiation while not affecting
oligodendrocyte precursor proliferation [46]. Oligodendrocytes synthesize myelin and thus
are the major lipid producing cells in the CNS. Interestingly, a majority of
the cells that are sensitive to PPARβ during their differentiation
(adipocytes, trophoblast giant cells, sebocytes, and keratinocytes) are characterized by lipid
accumulation during differentiation.
Indeed, disruption of
PPARβ resulted in an alteration of mouse adipose tissue development [7]. In 3T3-L1 and 3T3-F442A cell lines which
replicate in vitro adipocyte
differentiation, PPARβ is one of the early activated genes [51]. In contrast to this early implication in
adipocyte differentiation, PPARβ regulates the late stages of sebaceous cell
differentiation [52]. It is also the most effective PPAR isotype in
stimulating lipid accumulation in keratinocytes [53]. Finally, the differentiation of giant cells
in mouse placenta is accompanied by a PPARβ-dependent accumulation of lipid
droplets and an increased expression of the adipose differentiation-related
protein (ADRP, also called adipophilin), which may participate in lipid
metabolism and/or steroidogenesis [12]. While the specificity of each of these
contexts suggests that PPARβ acts on different programs of differentiation [54], this contribution of PPARβ to lipid synthesis
may well also apply in oligodendrocytes, accelerating their differentiation
from precursor to fully mature cells.PPARβ action on neuronal
differentiation is still under investigation. In primary cultures of embryonic
cortical neurons, PPARβ is expressed in the neuron nuclei and increases in
relation to the degree of maturation of these cells, in correlation with its
heterodimer partners RXR β and γ. The concomitant induction of the PPARβ target
gene ACS2 suggests that PPARβ is activated [20]. With respect to neuronal differentiation per se, the available data are
limited to human neuroblastoma cell lines. Exposure of these PPARβ expressing
cells to PPARβ agonists, either oleic acid or the GW610742X, triggers neuronal
differentiation [20], characterized by neuritis outgrowth. Both
compounds also promote morphological modifications of the actin filaments [55] and induce the expression of a series of
neuronal differentiation markers such as growth associated protein 43 (GAP-43),
neural cell adhesion molecule (N-CAM), and neurofilament-200 [55]. As the cells undergo differentiation, their
proliferation rate, cellular migration, and invasiveness are slowed down by
oleic acid or GW610742X treatments. In parallel, oleic acid or the GW610742X
agonist increases the expression of the cyclin inhibitor p16, indicating that
PPARβ activation may be able to promote cell cycle arrest [55]. All GW610742X effects are related to PPARβ,
as demonstrated by the use of siRNA silencing. In contrast, the oleic acid
effects were never fully reverted thereby indicating that they are only
partially mediated by PPARβ.These observations however need to
be confirmed in more physiological models, such as primary cultures of neurons
and mouse models. In fact, they contrast with other data suggesting that PPARβ
rather maintains neural stem cells in an undifferentiated, proliferative status [56]. In the model of neurospheres cultures,
prepared from the periventricular tissue of the adult mouse brain, western-blot
and RT-PCR analysis demonstrated that PPARβ is expressed in undifferentiated
neurospheres (S0) and decreases in differentiated neurospheres (S10) [45]. In line with this, the expression of PPARβ in
primary cultures of mouse cortical astrocytes also decreases between 14 and 21
divisions, possibly in relation to the decreased astrocyte proliferation at
confluence [45]. In these studies, PPARβ activity correlates with the expression of genes
involved in cell cycle [20, 45, 57]. Nevertheless,
PPARβ action on cell proliferation is highly dependent on the cell type. For
example, it exerts a proproliferative action on preadipocytes [58, 59] and an antiproliferative action on
keratinocytes [60]. Moreover, PPARβ proproliferative activity on
neural stem cells does not necessarily exclude a prodifferentiation activity.After this tour of the possible
functions of PPARβ in the brain, ranging from metabolism to neural cell fate,
the next sections of this review highlight the consequent roles of PPARβ in
brain alterations and repair.


## 5. PPARβ in Brain Ischemia

The role of PPARβ in brain repair was first addressed in a model of
focal cerebral ischemia, with a middle cerebral artery occlusion. Compared with
wild type, PPARβ-null mice exhibited a significant increase in the infarct size
[61, 62], suggesting that PPARβ exerts a neuroprotective
activity. Intriguingly, the difference in infarct size between wild-type and
PPARβ-mutant mice was detected by RMN as early as 30 minutes after performing
the ischemia [62], suggesting that PPARβ plays a role in the
very early events. Reciprocally, in a transient middle cerebral artery
occlusion, intracerebral infusion of L-165041 or GW501516 in rat ventricle
significantly attenuated the ischemic brain infarct size 24 hours after
reperfusion [63]. Several hypotheses concerning the molecular
mechanism of this neuroprotective activity are discussed below.An important activity of PPARβ is to  promote
cell survival under stress conditions, as demonstrated in keratinocytes during skin wound healing    [50] and in primary
keratinocyte   exposed to inflammatory signals [64].   PPARβ activation also promotes
renal cell survival following hypertonic stress [65] as well as oxidative stress [66]. Neural cells also seem to be sensitive to
PPARβ activation under stress conditions. In primary cultures of rat cerebellar
granule neurons, treatment with GW0742 significantly reduced cell death during
a 12-hour exposure to low-KCl media. However, prolonged incubation (48 hours)
with GW0742 produced significant inherent toxicity [67]. In
a different context, human neuroblastoma SH-SY5Y cells were exposed to a variety of chemicals provoking cell
death, such as thapsigarginand the endoplasmic reticulum calcium
ATPase inhibitor, 1-methyl-4-phenylpyridinium. Treatment with two PPARβ
agonists, L-165041 or GW501516, significantly attenuated cell death in a
concentration-dependent manner [63]. In
vivo, in a model of middle cerebral
artery occlusion, an
increase of malondialdehyde and a decrease of glutathione and manganese
superoxide dismutase in PPARβ-null mice argue for increased brain oxidative
stress. This phenotype was associated with a relative increase in interferon γ
but a lack of TNFα production [61]. Thus, PPARβ could regulate central
inflammation and antioxidant mechanisms in the damaged brain. Some known PPARβ-regulated
genes could explain these observations, including COX2 [68], which promotes inflammatory reactions by
prostaglandins synthesis [69]. Nevertheless, in vivo or in vitro
treatment of T cells with GW0742, a PPARβ selective agonist, did not reduce
IFNγ production [70]. Alternatively, PPARβ could also act via the
regulation of IL-1β to reduce astroglial and microglial inflammatory
activation, as suggested in experimental autoimmune encephalomyelitis (EAE) [70]. PPARβ inflammatory response could also
involve a direct interaction between PPARβ and the inflammatory suppressor
protein, BCL-6,  as in macrophages [71].While we can reasonably hypothesize
that PPARβ may indeed play a role in modulating inflammation and controlling
oxidative damages, thereby contributing to moderate ischemia lesion, other
hypotheses may also contribute to understanding the increased ischemic lesion
in PPARβ-null mice. An interesting one concerns the role of PPARβ in the
vascular system. For example, a different patterning of vascular territories
would result in a different infarct size occurring at the very first time point
postischemia. An experiment designed to visualize the vascular tree would then
provide an important control. Local conditions of blood flow might also affect
the outcome of an ischemia experience. However, no data so far have been
published concerning hemodynamic parameters in the brain of PPARβ-null mice.
Finally, angiogenesis itself might be concerned. This is supported by
investigations performed on an unrelated model, using subcutaneous inoculation
of lung carcinoma cells carrying the two PPARβ wild-type alleles in a PPARβ-null
mutant mouse. In this model, the tumor growth was impaired, due to the absence
of PPARβ in the stroma cells surrounding the developing tumor. This led to a
diminished blood flow and a reduced development of hyperplastic microvascular
structures [72]. Thus, PPARβ deletion could also affect the
delayed response to ischemia by impairing angiogenesis [73].An interesting cellular property that may be
overlooked in the search for functional disturbances linking PPARβ and cerebral
ischemia is cell-cell adhesion  and matrix-cell  adhesion. As proposed by
del Zoppo et al. [74], matrix
cell adhesion receptors might be
essential for the maintenance of the integrity of the blood-brain permeability
barrier, challenged upon local injury. In particular, focal ischemia suddenly
alters the matrix constituents and changes the expression of cell adhesion
receptors, locally increasing vascular permeability [75]. We summarize below some indirect evidence for
a role of PPARβ in cell adhesion, which may contribute to its neuroprotective
activity.In an in
vitro study, modulation of PPARβ activity in F9 teratocarcinoma cells
positively correlated with modulation of neural cell adhesion molecule (NCAM)
expression. In fact, F9 cells treated with valproic acid increased the
expression of PPARβ, but not that of PPARα or PPARγ, while also enhancing the expression of cell adhesion molecules such as
NCAM and PST1. Reciprocally, overexpression of a dominant-negative PPARβ
reduced the NCAM induction [76]. In endothelial cells of human umbilical,
PPARβ directly regulated a few key cell-adhesion genes. PPARβ agonists GW0742
and GW501516 significantly inhibited TNFα induced expression of vascular cell
adhesion molecule-1 and E-selectin, and the ensuing endothelial-leukocyte
adhesion [77]. Chromatin immunoprecipitation assays showed
that GW0742 switched the interaction of BCL-6, a transcription repressor, from
PPARβ to the vascular cell adhesion molecule-1 (VCAM-1) gene promoter. Evidence
for a role of PPARβ in cell adhesion/migration also stems from PPARβ activity
in wound healing, where it regulates the intracellular pathways activated
during keratinocyte directional sensing, polarization, and migration [16]. In these events, redistribution of integrins
requires Akt1 activity while NF-κB stimulates the production of the
metalloproteinase MMP-9, which allows the digestion of extracellular matrix, a
process required for cell migration. Since PPARβ concomitantly regulates both
Akt1 and NF-κB [64], it would be of great interest to study these
two pathways in the damaged brain.In a more general way, cell adhesion is a key
developmental process, as it determines the location of a cell by regulating
its capacity to move in a tissue or to be restricted to a defined area. It is
also crucial for neural cell-cell interactions, including axon guidance and
synapse formation, processes tightly connected to the functioning of the brain
itself, such  as learning and memory. Taking these observations together points to
the particular need for a better understanding of PPARβ action on neural cell
adhesion.


## 6. Using PPARβ Agonist/Antagonist to Treat Brain Diseases

Whereas many studies have explored the possible benefits of targeting
the ever popular PPARγ isotype with regard to its neuroprotective effect [78], an interest in the more ubiquitous PPARβ isotype
is  recently emerging. In this last
section, we will therefore review studies that have explored PPARβ targeted
therapeutics for a variety of brain diseases.Experimental autoimmune encephalomyelitis (EAE) [79, 80] is a
T-cell mediated autoimmune disease that involves inflammatory activation of
brain glial cells, and is used as a model for multiple sclerosis. Oral
administration of PPARγ agonists reduces the incidence and severity of
clinical, histological, and biochemical symptoms in EAE. The GW0742 PPARβ
agonist has also beneficial effects, demonstrated in a mouse model of EAE, in
which mice were immunized with an encephalitogenic myelin oligodendrocyte
glycoprotein (MOG) peptide [70]. When given at the time of immunization,
GW0742 had only a moderate effect on the appearance and severity of clinical
symptoms. Nevertheless, prolonged treatment of mice already exhibiting signs of
the disease improved their clinical status. Intriguingly, the clinical
improvement of cortical lesions contrasts with no significant reduction of the
cerebellar lesions. The mechanism does not involve T cell activation,
oligodendrocyte maturation, or survival, but probably a reduction of astrocyte
and microglial inflammatory responses [70]. Thus, PPARβ and PPARγ agonists differ both in the timing of
treatment efficiency and the molecular mechanism involved [81].The absence of PPARβ agonist action on
oligodendrocyte maturation or survival in this model of EAE is surprising (see Section 4). It is thus
tempting to explore how the PPARβ agonist could alter the course of a
nonautoimmune demyelinating disease, such as a diabetes complication or
leukodystrophy.
In particular, adrenoleukodystrophy is a rare
inherited disorder that leads to progressive failure of the adrenal gland, brain damage, and eventually death. In this
disease, the mutation of the ATP-binding cassette subfamily D member 1 (ABCD1)
gene leads to a reduction of beta oxidation in peroxysomes with the
accumulation of very long chain fatty acids in the adrenal cortex and brain,
causing a progressive inflammatory demyelination. Because of its crucial role
in peroxisome proliferation and fatty oxidation, PPARα was the prime target
tested in a therapeutic approach. However, no direct effect of PPARα agonists
could be seen in modulating ABCD2, the closest relative of ABCD1, in the brain [82]. It would still be interesting to test a PPARβ
agonist because of its combined role in fatty acid oxidation and in
oligodendrocyte maturation.Alzheimer disease is a neurodegenerative
disorder characterized by cognitive and memory deterioration, progressive
impairment of activities, and a multiplicity of behavioral and psychological
disturbances. While not fully understood, the mechanism of the alteration
includes an extracellular accumulation of amyloidal plaque formed by
oligomerisation of the amyloidogenic peptide Aβ 1–42, and the accumulation of
the Tau protein responsible for neurofibrillar degeneration. Interestingly, the
noradrenalin (NA) neurotransmitter protects neurons from inflammation [83], via a mechanism that is partially PPARβ
dependent. In fact, in the model of primary cultures of rat cortical neurons
exposed to oligomeric amyloid beta, NA partially reduced neuronal damage and
toxicity, as assessed by a reduction in the release of LDH. Interestingly,
there was a concomitant two fold induction of PPARβ mRNA and protein levels. The
NA neuroprotective effects were partially blocked by cotreatment with a PPARβ
selective antagonist. Moreover, the selective PPARβ agonist GW742 reduced LDH
release to the same extent as did the NA, suggesting that PPARβ is the main
mediator of NA action [84]. Nevertheless, high concentrations of GW742
(50 μM) are required in order to observe this effect [85], and further in vivo studies are required to evaluate the true potential of
PPARβ agonists as therapeutic tools for Alzheimer disease.Finally, PPARβ agonist treatment could be
beneficial in another notorious neurodegenerative disorder: Parkinson disease,
characterized by the disappearance of the dopaminergique neurons with
alteration of the nigrostriatal pathways. Beside the classic occurrence of
Parkinson disease, whose etiology is mainly unknown, the synthetic opiate
1-methyl-4-phenyl-1,2,3,6-tetrahydrodropyridine (MPTP) causes Parkinsonism in
young drug-addicted individuals. Iwashita et al. showed that an L-165041or GW501516 intracerebroventricular
infusion 48 hours before the first injection of MPTP protects
against depletion of striatal dopamine and its metabolites [63].These different studies highlight the need to characterize
and optimize some PPARβ agonists for their capacity to cross the blood-brain
barrier in order to treat various acute and chronic brain disorders.


## 7. Conclusion

This review highlights the few data available on PPARβ activity in the
brain. While sometimes highly speculative, it underlines the good reasons to
pursue dedicated research in this domain. The brain is the second most
lipid-enriched tissue after adipose tissue. Products of fat metabolism, free-fatty
acids, ketone bodies, and glycerol dominate metabolic pools in early
development, as a consequence of the milk diet. The high expression of the
PPARβ lipid sensor during brain maturation suggests that it is a key regulator
of brain metabolism during neurodevelopment. Moreover, PPARβ anti-inflammatory
and prosurvival activities may play a prominent role in the acute phase of
brain injury.  In addition, PPARβ
prodifferentiation activity, in particular on oligodendrocyte lineage, is of
potential benefit in the treatment of neurodegenerative diseases. Therefore, in
view of its potentially wide therapeutical use, it appears crucial to carry out
in depth studies of the basic mechanism of PPARβ activity, in order to
understand the molecular network driven by this receptor in the brain.



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