PPAR Research

PPAR Research / 2018 / Article

Review Article | Open Access

Volume 2018 |Article ID 2010675 | https://doi.org/10.1155/2018/2010675

Manoj Govindarajulu, Priyanka D. Pinky, Jenna Bloemer, Nila Ghanei, Vishnu Suppiramaniam, Rajesh Amin, "Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease", PPAR Research, vol. 2018, Article ID 2010675, 20 pages, 2018. https://doi.org/10.1155/2018/2010675

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

Academic Editor: Paul D. Drew
Received18 Jun 2018
Revised31 Aug 2018
Accepted13 Sep 2018
Published21 Oct 2018


Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

1. Introduction

Alzheimer’s disease (AD) is the sixth leading cause of mortality in the United States. In 2018, an estimated 5.7 million Americans of all ages are living with Alzheimer's dementia and this is projected to increase to 14 million by 2050 [1]. However, there are limited options to prevent the progression of the disease. Moreover, the continuous increase in mortality rates due to AD reinforces the critical need for identifying novel molecular targets with therapeutic potential. For example, the failure of several recent potential therapies in clinical trials for improving cognitive deficits in AD by reducing amyloid beta (Aβ) levels, suggests a need to explore alternative approaches for AD treatment that are not focused upon altering Aβ levels.

Pathological correlations between type 2 diabetes mellitus (DM) and AD provide direct links for the development of cognitive deficits in both diseases and suggest potential application of antidiabetic drugs for AD [2, 3]. Type 2 DM is a disorder of altered glucose regulation and is associated with cognitive decline [4]. Although there are direct links between AD and DM in the manifestation of cognitive impairment, there is an understanding that impaired insulin signaling directly alters memory in AD. Insulin signaling in the brain has a significant role in modulating neuroendocrine and neurotrophic functions including synaptic plasticity [5, 6]. Therefore, extensive investigation of these correlations between the two diseases will potentiate the identification of novel therapeutic targets for the treatment of AD.

Peroxisome proliferator-activated receptors (PPARs), a subfamily of nuclear receptors, play a crucial role in regulating insulin sensitivity and may serve as potential therapeutic targets for AD. Recently, pharmacological activation by a class of PPAR subtype, PPARγ agonists thiazolidinediones (TZDs), has been found to improve learning and memory in transgenic AD animal models [7, 8]. Furthermore, meta-analysis studies indicate that pioglitazone treatment may offer therapeutic benefits in patients with early or mild-to-moderate AD [9]. Further analysis of these studies showed a significant reduction in amyloid beta and tau pathology measured in cerebral blood flow samples from AD patients. The anti-inflammatory properties and improved glucose metabolism by TZDs have helped explain how it improves cognition in AD patients and transgenic animal models of DM and AD [10, 11]. However, the molecular signaling mechanisms mediated by central PPARγ activation resulting in improved cognition in AD have not been extensively investigated. Furthermore, the use of these drugs for cognitive deficits in diabetes and AD is limited due to their poor bioavailability in the brain and off-target effects [12, 13]. Therefore, there is a critical need to develop PPARγ targeted agents that display improved tolerability. To understand the significance of these chemical and pharmacological standpoints, the molecular structure and how PPARγ modulates different cellular targets need to be more thoroughly evaluated.

Recently, the focus of PPARγ has intensified, as new ligands and novel biological roles have emerged for the receptor activity, particularly for its therapeutic potential in neurodegenerative disorders, such as AD. The present review discusses the beneficial role of PPARγ ligands on the pathologies of AD and the therapeutic potential of selective PPARγ modulators as future therapy for AD.

2. Overview of PPARs

2.1. Isoforms and Expression

The PPARs are part of a subfamily of nuclear receptors that regulate several important cellular processes by activating or repressing transcription via their ligand binding domain (LBD) and DNA-binding domains (DBD) [14]. The initial PPAR (PPARα) was cloned as a nuclear receptor from a mouse-liver genetic (cDNA) library that was activated by several endogenous and xenobiotic compounds known as peroxisome proliferators. PPARs are named for their property of increasing both the number and activity of liver peroxisomes after administering high dose of these substances for a chronic time frame in rodents. Additionally, marked liver abnormalities progressing to liver carcinomas were noted, indicating that these substances at high doses strongly induce peroxisome proliferation [15].

The PPARs are mainly divided into PPARα, PPARβ/δ, and PPARγ. All the PPARs consist of distinct functional domains including an N-terminal transactivation domain (AF1), a highly conserved DBD, and a C-terminal ligand binding domain (LBD) that contains a ligand transactivation function (AF2). Each subtype displays distinct effects on the body; for example, PPARα regulates whole body energy homeostasis by reducing lipid levels, regulating glucose homeostasis, and reducing insulin resistance [16]. PPAR β/δ regulates lipid metabolism and myelination in the brain while PPARγ regulates lipid and glucose homeostasis, mitochondrial biogenesis, and inflammation [17].

The PPARγ receptor is unique in that despite being expressed from the same gene, it has different promoters and 5′-exons. Hence, it consists of three isoforms, namely, PPARγ-1, PPARγ-2, and PPARγ-3. PPARγ-1 and PPARγ-3 are similar, while PPARγ-2 differs in the ligand-independent region at the N-terminus. PPARγ-2 has an extra 30 amino acid residues in the amino end, which provides a potent transcriptional activity compared to PPARγ-1 [18]. PPARγ-1 is expressed in almost all cells while PPARγ-2 is restricted in the adipose tissue [19]. In the CNS (central nervous system), all the three subtypes of PPARs are expressed, with PPAR β/δ being the most abundant subtype [20, 21]. PPARα is involved in acetylcholine metabolism, excitatory neurotransmission, and oxidative stress defense [22]. PPARβ/δ is ubiquitously expressed in all cell types including immature oligodendrocytes and promotes differentiation and myelination in the CNS [23, 24], while PPARγ is expressed predominantly in microglia and astrocytes and regulates inflammation in the CNS [25].

2.2. PPAR Signaling

PPARs regulate the expression of various genes through a complex set of mechanisms. The homo PPAR forms a heterodimer with another class of nuclear receptors, retinoid X receptors (RXR). During unstimulated conditions, the heterodimer complex is associated with corepressors (NCoR and SMRT), which suppress gene transcription [26]. Ligand binding to the hydrophobic pocket of the PPAR receptor induces conformational changes in the LBD structure, thereby resulting in its activation. Changes in the conformation on ligand binding lead to release of corepressors NCoR/SMRT or Not1, which generally prevents gene transcription, respectively. Release of corepressor with full agonist results in the stabilization of the LBD, resulting in binding of coactivators CBP/P300, p160/SRC-1, and vitamin D receptor interacting protein (DRIP) or thyroid hormone receptor associated protein (TRAP) complexes resulting in the activation of the PPAR molecule. Once activated, the PPAR/retinoid X receptor heterodimer stimulates peroxisome proliferator response elements (PPRE) in the promoter region of target genes. This scaffold recruits histone acetyl transferases and the gene transcription machinery (RNA polymerase complex), which together initiate chromatin relaxation to permit transcription of target genes [27] as depicted in Figure 1. Coactivator PGC-1α gene expression is particularly important in mediating cognition and has shown protective effects against AD. In addition, it regulates mitochondrial biogenesis, oxidative metabolism, fatty acid oxidation, and gluconeogenesis via PPARs; these effects on mitochondria, in turn, can improve brain function [28].

Apart from the above-mentioned action of PPARs involving gene transcription in the nucleus, nongenomic actions associated with the cytoplasmic PPARs have been observed. Nongenomic regulation of PPARγ is mediated by interaction with cytosolic second messengers, including kinases and phosphatases [29]. For instance, in response to mitogen stimulation, the MAP/ERK kinase, MAPK kinase (MEK)-1, binds directly to the AF2 domain of PPARγ, leading to the sequestration of PPARγ in the cytoplasm. Selective inhibition of this MEK1/PPAR interaction has been proposed to offer novel pharmacological treatments of various cancers, metabolic disorders, and inflammation [30]. Recent studies indicate that posttranslational control of PPARs occurs through phosphorylation, SUMOylation, ubiquitination, and nitration [31]. The phosphorylation of PPARγ occurs at several sites via different kinases including MAPKs. An N-terminal serine phosphorylation (Ser82 in PPARγ-1 and Ser112 in PPARγ-2), mediated by MAPKs, reduces the transcriptional activity of PPARγ-1 and PPARγ-2 (in cells activated by serum) [32, 33]. Phosphorylation as a mechanism of action of PPARγ agonists has been recently suggested linking its role to obesity, inflammation, and insulin resistance [34]. For instance, rosiglitazone was found to inhibit phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue. This leads to transcription of insulin-response genes (such as adiponectin and adipsin) thereby mediating antidiabetic effects. As CDK5 is activated by inflammatory mediators, targeting CDK5/PPARγ regulation may offer new avenues in treating various disorders where inflammation is a key component. SUMOylation is a posttranslational modification that regulates the stability, nuclear/cytosolic ratio, and activity of several transcription factors. Of importance is the transcriptional repression of inflammatory genes such as inducible nitric oxide synthase (iNOS) and TNF-α, which are regulated by NF-kB pathway. Additionally, SUMOylation also induces recruitment of PPAR corepressors, such as NCoR as depicted in Figure 2.

The LBD of PPARγ consisting of the transcriptional AF2 motif associated with helix 12 mediates most of the pharmacological actions of PPARγ agonists [47]. The importance of AF2 motif in regulating PPARγ targeted genes has been extensively studied, thereby allowing us to understand the mechanism of ligand-induced transcriptional activation by PPARγ [48, 49]. AF2 helix is in an equilibrium state between closed (active) and open (inactive) conformations in the absence of the ligand [50]. However, binding to a full agonist leads to AF2 helix getting locked in closed (active) state, thereby allowing recruitment of coactivators for transcriptional activation [51]. Hence, developing novel PPARγ ligands that stabilize the AF2 helix in distinct states between closed and open conformations would offer therapeutic advantage which is discussed in subsequent sections.

Several studies have reported that the locking of AF2 helix in its closed conformation is responsible for the antidiabetic effects as well as several side effects noted with PPARγ agonists like TZDs [5254]. Hence, developing novel PPARγ ligands that stabilize the AF2 helix in distinct states between the closed and open conformations will selectively recruit coactivators for newer therapeutic benefits with reduced side effects [5557].

Recently, several natural and synthetic PPARγ agonists have been developed to treat various disorders, out of which the selective PPARγ modulators (SPPARγMs) have attracted considerable attention because of their ability to selectively target PPARγ activity states, thereby offering therapeutic efficacy with minimal side effects [5861]. Currently, no SPPARγMs have been successfully used in clinical practice, and mechanistically it remains unclear how to achieve selective PPARγ activation. The subsequent sections discuss the role of PPARγ in modulating the pathologies of AD followed by SPPARγMs under development for treating AD.

3. Overview of AD

Pathological changes related to AD occur many years before clinical symptoms are present. The traditional theory for the development of AD has been the amyloid beta cascade hypothesis, which postulates that pathogenic amyloid beta is the primary cause for development of AD and leads to the hyperphosphorylation of tau protein. However, it is becoming increasingly clear that a multitude of pathological mechanisms are likely at play to promote development of clinical AD [62]. Therefore, therapeutics with multiple mechanisms of action against AD pathology may be desirable in treatment of the disorder. Some early pathological processes which are increasingly recognized to contribute to AD include neuroinflammation [63], mitochondrial dysfunction [64], and dysregulated insulin signaling [65]. Amyloid beta accumulation occurs prior to clinical symptoms and persists throughout the course of the disease. Occurrence of memory dysfunction later in the disease is correlated with the severity of synaptic deficits and severity of tau pathology [66]. Therefore, an ideal AD drug may target multiple facets of the disease including inflammatory and metabolic components occurring early in disease, along with reducing pathogenic amyloid beta, hyperphosphorylated tau, and synaptic dysfunction later in the disease. In fact, PPARγ signaling exerts several potential beneficial mechanisms in early, as well as in late, AD, as it reduces inflammation, improves metabolic processes, and may directly reduce levels of pathogenic amyloid beta and hyperphosphorylated tau. The hallmarks of AD relating to its pathologies are illustrated in Figure 3.

4. PPAR in Alzheimer’s Disease

4.1. Genetic Alterations Relating PPARγ to AD

Genome-wide association studies (GWAS) indicate a strong association between late onset Alzheimer’s disease (LOAD) and over twenty genomic loci [67, 68]. One of the strongest genetic risk factors of LOAD is ApoE, and the presence of the ApoE4 allele is associated with an increased accumulation of Aβ. Several studies have shown increased ApoE-mRNA levels in LOAD brains and that cis-genetic variability contributes to differential ApoE gene expression [6971]. Furthermore, chromosome 19q13.32, a gene rich region consisting of TOMM40, ApoE, and APOC1 genes, is implicated in several phenotypes including AD. This region exhibits a complex regulation and is enriched in potential PPARγ binding sites. PPARγ agonists decreased the levels of the TOMM40, ApoE, and APOC1-mRNAs, with the greatest effect on ApoE-mRNA through transcriptional regulation [72]. Furthermore, a study done by Barrera et al. investigated the effect of PPARγ knockdown on expression of twenty-four late onset AD-associated genes and demonstrated that PPARγ regulates the expression of seven LOAD-associated genes. Upregulation of six genes (ABCA7, ApoE, CASS4, CELF1, PTK2B, and ZCWPW1) and downregulation of one gene (DSG2) were noted and indicate that PPARγ agonists may represent an attractive class of drugs for preventing or delaying the onset of late onset AD [73].

4.2. PPARγ in Early Stages of AD
4.2.1. PPARγ and Amyloid Beta

AD is pathologically characterized by deposition of extracellular fibrillar amyloid derived from proteolytic cleavage of amyloid precursor protein (APP) and formation of senile plaques. An imbalance between Aβ production and its clearance leads to Aβ accumulation, which further leads to tau hyperphosphorylation and neurodegeneration [74]. PPARγ agonists have also been observed to reduce Aβ levels either by reducing the Aβ production or enhancing its clearance. Several studies have demonstrated the role of PPARγ agonists in decreasing Aβ accumulation. For instance, pioglitazone-treated APP transgenic mice showed reduced transcription and expression of β-secretase enzyme that processes APP to generate Aβ [75]. However, other studies have shown that APP processing and Aβ production are not affected by pioglitazone suggesting that decrease in Aβ levels by PPARγ agonists may be due to Aβ clearance [76].

Aβ clearance in the brain is mediated by enzymatic and nonenzymatic pathways. Some of the key enzymes include insulin-degrading enzyme (IDE), neprilysin (NEP), and matrix metalloproteinase (MMP)-9. The nonenzymatic pathway includes (1) drainage through perivascular basement membranes, (2) phagocytosis by microglia or astrocytes, and (3) clearance mediated by receptors such as low-density lipoprotein receptor-related protein 1 (LRP1) and P-glycoprotein localized predominantly on the abluminal side of the cerebral endothelium [77, 78].

LRP1 is important in mediating endocytosis of various proteins such as ApoE and Aβ.

Low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a transmembrane receptor involved in the endocytosis of more than 40 structurally different ligands, including ApoE, and Aβ peptide [79, 80]. Levels of LRP1 are found to be decreased in AD patients indicating its role in mediating Aβ metabolism. PPARγ transcriptionally regulates LRP1 gene due to the presence of PPRE on the LRP1 promoter region [81]. A study by Rondon-Ortiz et al. reported that rosiglitazone transcriptionally activated LRP1 gene in a concentration dependent manner in HepG2 cells [82]. Similarly, rosiglitazone upregulated LRP1 expression at both the mRNA and protein levels, via PPARγ activation [83]. In vivo studies utilizing AD models need to be performed to validate the role of PPARγ agonists and LRP1 in AD.

Apolipoprotein E (ApoE) is a lipoprotein expressed predominantly in the brain and is known to enhance Aβ degradation and phagocytosis in the microglia and astrocytes [74]. PPARγ agonists (rosiglitazone and pioglitazone) have also been shown to induce Aβ degradation by increasing apolipoprotein E (ApoE) concentrations in the brain [76]. ApoE can increase the concentration of Aβ degrading enzyme neprilysin and insulin in astrocytes and microglia facilitating Aβ degradation [84]. In a recent study utilizing APP/Presenilin-1 mouse model [85], activation of PPARγ enhances the microglial uptake of Aβ resulting in reduced cortical and hippocampal Aβ level. This effect is mediated by scavenger receptor CD36, which is a well-known player of phagocytosis. This finding can be further confirmed by observance of reduced microglial response to fibrillar Aβ response in CD36 null mice [86]. Additionally, pioglitazone treatment on APP/PS1 mice increased the levels of ATP-binding cassette transporter (ABCA1) and ApoE, thereby decreasing the levels of Aβ by 50%. In addition, the expression and processing levels of APP and of Aβ-degrading enzymes were not altered, suggesting that the changes seen in amyloid deposition were a result of Aβ catabolism [87]. Similar results were obtained with rosiglitazone treatment in a J20 mouse model [88] and with the APP/PS1 mice [89]. These studies suggest that TZDs enhance amyloid clearance in cell lines of microglia and astrocytes treated with Aβ and these effects are related to the activation of the ApoE pathway. Interestingly, rosiglitazone improved cognition in mild-to-moderate AD patients that did not carry ApoE4 allele. In contrast, no improvements were noted in cognitive test in ApoE4 positive patients, indicating that the amyloid clearance pathway dependent on TZDs also depends on the expression of functional ApoE4 [36]. The compelling results from animal models of Alzheimer’s disease underline the beneficial effects of PPARγ agonists on attenuating Aβ pathologies for future therapies.

4.2.2. PPARγ and Neuroinflammation

Several failures in AD clinical trials have encouraged researchers to look at treatment in the presymptomatic phase, where inflammation plays a vital role in the progression of neurodegeneration. One of the many potential beneficial effects of PPARγ is its ability to downregulate inflammatory gene expression in immune cells [90, 91]. For example, PPARγ activation has been shown to modulate the microglial response to amyloid deposition in such a way that it increases Aβ phagocytosis and decreases cytokine release [85]. The inflammatory hypothesis of AD involves activation of glial cells (microglia and astrocytes) by Aβ, which produces proinflammatory substances as a driving factor for neurodegeneration. Interestingly, a large meta-analysis reported that use of nonsteroidal anti-inflammatory drugs (NSAIDs), many of which have been shown to directly activate PPARγ, is associated with a reduced risk of developing AD [92]. NSAID medications have provided key evidence that AD progression or initiation is related to neuroinflammation and that PPARγ may mediate beneficial properties of NSAIDs in relation to AD. Commonly used NSAIDs including ibuprofen, indomethacin, and sulindac have been demonstrated to activate PPARγ [93]. Under physiological conditions, the expression of PPARγ in the brain is relatively less. However, its expression as measured by mRNA levels is elevated in AD patients, suggesting that PPAR may play a crucial role in modulating the pathology of AD [94]. Collectively, these findings led to the concept that PPARγ could be an important target for mitigating brain inflammation in AD. More specifically, the activation of PPARγ suppressed various transcription factors involved in inflammation such as nuclear factor-kB (NF-kB), Stat-1, and transcription factors activator protein-1 [95] which are important proinflammatory genes as illustrated in Figure 4.

Additionally, PPARγ also downregulates cyclooxygenase-2 (COX-2), metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), proinflammatory cytokines, chemokines, and interleukins [9698]. Thus, a reduction in PPARγ activation may contribute to chronic inflammation, and pharmacological treatment with PPARγ agonists may diminish expression of inflammatory genes. Several PPARγ ligands, both natural (15d-PGJ2, docosahexaenoic acid) and synthetic (NSAIDs and TZDs), were shown to inhibit the expression of interleukin-6 (IL-6), TNFα, and cyclooxygenase-2 (COX-2) from monocytic and microglial cell cultures stimulated with Aβ [99]. Similarly, the anti-inflammatory effects of PPARγ agonists like rosiglitazone and pioglitazone were noted in several AD mouse models [100, 101]. For example, the treatment with pioglitazone reduced astrocytes and microglial activation in the cortex and hippocampus of the A/T mouse that expresses high levels of Aβ and TGF-β1 [87]. At the same time, injection of rosiglitazone into the brain of Wistar rats, previously treated with Aβ oligomers, prevented the increase of inflammatory cytokines levels resulting in an improvement in cognitive decline and prevention of microglia activation [102]. Interestingly, similar effects were also observed in the AD transgenic mouse models J20 and APP/PS1 with oral administration of rosiglitazone [88]. Targeting microglia and astrocyte polarization may serve as therapeutic option. Cyclin-dependent kinase 5 (CDK5) is involved in activation of microglia and astrocytes and may serve as a potential therapeutic target for PPARγ agonist therapy. This possibility is supported in a report where pioglitazone treatment, in conditional CDK5 knockout mice, displayed significant reduction in the activation of microglia and astrocytes and neuronal loss resulting in improved survival rates [103]. Mechanistically, CDK5 is a protein kinase, whose dysregulation contributes to synaptic loss and tau hyperphosphorylation in the AT8 epitope (present in the AD brain) after stimulation of Aβ fibrils [104, 105]. Together, these findings suggest that an anti-inflammatory property by TZDs involves regulating microglia and astrocytes inflammation and may involve CDK5.

Recently, PPARγ has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in several neurodegenerative diseases. M1 microglia have proinflammatory and neurotoxic properties through secretion of proinflammatory cytokines (interleukin IL-1α, IL-1β, TNF, and NO) [106, 107]. Alternatively, activated M2 microglia exhibit an anti-inflammatory phenotype and neurotrophic effect and degrade toxic aggregates due to anti-inflammatory interleukin production [106, 107]. The importance of PPARγ in regulating the M1/M2 phenotypic switch has been confirmed by Amine Bouhlel et al., who demonstrated that activation of PPARγ potentiates the polarization of circulating monocytes to macrophages of the M2 phenotype [108]. Subsequent studies reported that an active PPARγ pathway is a prominent feature of alternatively activated (M2) macrophages and that M2-type responses are compromised in the absence of PPARγ expression. PPARγ expression is important for the full expression of certain genes characteristic of M2 macrophages, especially the gene encoding arginase-I, a direct PPAR target [109].

The small molecule SNU-BP was recently observed to inhibit inflammatory cytokine production and iNOS activity in LPS-stimulated microglia by PPARγ activation [110]. In addition, SNU-BP also increased IL-4 and arginase-1 expression, which are considered as M2 microglial phenotype markers; thus SNU-BP further evaluation of in vivo testing will help decipher a novel mechanism for this compound for mitigating early AD. Conversely, 12-month-old APP/PS1 mice treated with pioglitazone showed a significant reduction of the immunofluorescence intensity of microglial activator marker M1 in the surrounding area of amyloid deposits and elevated expression of M2 markers. Reduction in the levels of GFAP-immuno-reactive astrocytes surrounding amyloid plaques and internalized Aβ peptides in astrocytes of pioglitazone-treated animals were noted. Together, these findings suggest that TZDs treatment not only reduced the inflammatory response by microglia and astrocytes but also facilitated the removal of Aβ deposits presumably through enhancing the phagocytic activity of these cells.

Interestingly, some of the anti-inflammatory effects of PPARγ agonists appear to be independent of PPARγ activity. For instance, the rank order potency of drugs that activate PPARγ is often inconsistent with the anti-inflammatory efficacy, and expression of PPARγ does not correlate with the observed anti-inflammatory effects. Moreover, part of the anti-inflammatory effects of TZDs is unaffected in PPARγ knockout models, and secretion of both IL-6 and TNF-α is inhibited equally in both wild type and PPARγ deficient macrophages [111]. Together, these data indicate that some anti-inflammatory effects of TZDs may be due to PPARγ independent effects, thus suggesting that there exists a significant gap in understanding the mechanisms to explain how TZDs and PPARs confer their anti-inflammatory properties for AD and thus warrant further investigation.

4.2.3. PPARγ and Mitochondrial Function

Apoptosis, programmed cell death, is thought to be intimately involved in AD pathogenesis. Aβ localized to the mitochondrial membrane can initiate the intrinsic apoptotic pathway causing neuronal cell death [112]. Dysregulated metabolism results from altered mitochondrial trafficking and enhanced mitochondrial degradation, which can lead to alteration in tau and microtubular instability [113]. Increasing evidence suggests that PPAR ligands are involved in mitochondrial regulation in adipose tissue [114, 115] and other organs [116, 117] indicating a potential benefit against mitochondrial dysregulation in AD. PPAR-γ coactivator 1 alpha (PGC1-α) is highly expressed in the brain and acts as a critical transcriptional coactivator for mitochondrial biogenesis and cellular energy metabolism. Decreased hippocampal PGC1-α has been observed in postmortem analysis of AD patients [118]. Decreased PGC1-α expression has been reported to result in reduced mitochondrial density in various brain areas, including midbrain, cortex, and cerebellum accompanied with reduced ATP levels [119]. Both PPARα and PPARγ agonists prevent mitochondrial size reduction by enhancing PGC1-α expression in cultured hippocampal neurons [120]. In the APP23 mouse model of AD, PGC1-α gene delivery improves spatial and recognition memory along with reduction in Aβ level through a decrease in BACE1 activity [121]. However, excess PGC1-α can also exert deleterious effects via mitochondrial proliferation and produce toxicity in the heart [122], muscles [123], and brain, leading to cognitive impairment [124, 125]. Therefore, an ideal therapeutic approach would be to increase the PGC1-α level via an indirect mechanism, i.e., through PPAR ligands. Studies on N2A cells showed that treatment with rosiglitazone increased mitochondrial mass and function through the activation of PGC1-α mediated by the PKA/CREB/AMPK pathway [126]. In another study, chronic treatment with pioglitazone attenuated oxidative damage, restored mitochondrial respiratory activity, and enhanced mitochondrial biogenesis in Wistar rats injected with Aβ [127]. Taken together it can be stated that further research for novel therapeutic development of PPAR compounds will explore how these ligands will enhance mitochondrial function.

4.2.4. PPARγ, Insulin Signaling, and Brain Insulin Resistance

Insulin signaling is known to play a crucial role in the process of memory formation as insulin receptors are densely located in key areas of the brain, namely, olfactory bulb, hypothalamus, hippocampus, cerebral cortex, striatum, and cerebellum [128131]. Insulin is essential to maintain normal neuronal homeostasis and survival, thus promoting learning and memory specially in the hippocampus [132]. For instance, brain specific insulin receptor knockout animal model showed increased tau hyperphosphorylation with altered Akt and GSK3β expression [133]. Additionally, diet induced insulin resistance in AD mice displayed increased Aβ peptide and advanced plaque formation [134]. These studies indicate that insulin resistance serves as an underlying mechanism for the development of Aβ production in the brain and associated sporadic memory impairment [135, 136].

Postmortem studies in AD patients have shown significantly reduced levels of insulin as well as insulin like growth factor (IGF-1 and IGF2) and insulin receptor substrate-1 (IRS-1) in the brain [137]. Abnormal insulin signaling leads to impaired neuronal oxidative metabolism [138]. The increase in oxidative stress and mitochondrial dysfunction can lead to aberrant posttranslational modification of APP and accumulation of Aβ in neurons [139]. Because of these shared features between AD and diabetes, AD has also been referred to as type III diabetes mellitus, leading to a growing interest in using insulin sensitizing agents as a potential therapy for AD [100, 140]. Rosiglitazone, a PPARγ agonist, improved neuronal insulin resistance in high fat diet rat model by increasing the phosphorylation of AKT/PKB at Ser473. Additionally, high fat diet induced brain mitochondrial dysfunction and oxidative stress were attenuated by rosiglitazone [141].

The Wnt signaling pathway is important in mediating several functions in the central nervous system, including neuroprotection and synaptic plasticity, and deregulated Wnt signaling has been shown to be associated with AD [142]. Dysfunctional Wnt signaling is associated with Aβ deposition, tau hyperphosphorylation, and cognitive impairment as reviewed by Tapia-Rojas et al. [143]. In view of the energy dysregulation associated with AD, Wnt signaling has been shown to act as a central integrator of metabolic signals from peripheral organs to the brain, thereby promoting adequate glucose utilization in the neurons [144]. Furthermore, dysfunctional glucose utilization is also associated with several neurological disorders, indicating that Wnt signaling is important in AD pathogenesis [145, 146]. These findings suggest that pharmacological activation of Wnt pathway would be a feasible therapeutic approach for the treatment of AD.

4.3. PPARγ in Later Stages of AD
4.3.1. PPARγ and Tau

Tau proteins are microtubule associated proteins that under normal physiological conditions interact with tubulin for microtubule assembly by mediating microtubule stabilization [147]. However, under pathological conditions such as AD, tau proteins undergo hyperphosphorylation resulting in neurotoxicity. Homeostasis maintained between kinase-mediated phosphorylation and protein phosphatases-mediated dephosphorylation is important in regulating the phosphorylation state of tau protein [148]. Various important kinases regulate tau phosphorylation, including cyclin-dependent kinases (CDK2 and CDK5), GSK-3β, mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), Akt, protein kinase a (PKA), and calcium-calmodulin protein kinase 2 (CaMKII). Contrarily, PP1, PP2A, PP2B, and PP2C are important phosphatases that contribute to dephosphorylation of tau. Recent studies have shown that PPARs can also exert an effect on tau pathology. In vitro cellular studies using troglitazone and pioglitazone revealed reduced hyperphosphorylation of tau at Ser202, Ser396, and Ser404 in a tau transfected cell model involving GSK3β [149]. In the 3xTg-AD mouse model, treatment with pioglitazone resulted in significantly reduced tau phosphorylated-positive neurons in the hippocampus and improved cognitive deficits [150]. These studies also revealed that treatment with pioglitazone reduced tau phosphorylation at Ser202, Ser396, Ser404, Ser422, and Thr231 in cerebral cortex and CA1 area of hippocampus. Although these findings suggest that PPARγ stimulation can reduce tau hyperphosphorylation, further mechanistic studies are needed to determine the signaling mechanism by which PPARγ offers neuroprotection against tau hyperphosphorylation. Interestingly, the pan-PPAR agonist bezafibrate was shown to reduce tau phosphorylation in a P301 mice model by reducing iNOS and cyclooxygenase-2 in microglia [151]. Although role of PPARγ in Aβ mediated pathogenesis is exhaustively studied, its role in tauopathy needs to be explored for potential mechanism for reducing the hyperphosphorylation in-depth. A great variation can be noticed in the existing literature which is likely due to variation in the animal model studied and the time point of study.

4.3.2. PPARγ and Synaptic Plasticity

Moderate to severe stages of AD are characterized by synaptic failure which leads to cognitive decline and memory dysfunction. Synaptic function is dependent on specialized structures on neuronal processes called dendritic spines, and the loss of dendritic spines directly correlates with the loss of synaptic function. One of the key mediators for increasing dendritic density and synaptic plasticity is neurotrophins, including brain-derived neurotrophic factor (BDNF) [152]. Several studies have reported beneficial effects of PPARγ agonists in improving synaptic plasticity. Rosiglitazone has been shown to prevent dendritic spine loss and improve synaptic function in hippocampal neurons treated with Aβ oligomers [126]. Decreased expression of BDNF mRNA and protein levels were noted in hippocampi of db/db mice which were restored with rosiglitazone treatment. Furthermore, PPARγ has been shown to transcriptionally regulate BDNF expression as demonstrated from promoter activity assays wherein ligand activation of PPARγ induced the BDNF promoter in a log dose-dependent manner [153]. Similarly, Aβ injected rats treated with pioglitazone had reduced caspase-3 activation and increased BDNF levels, which was correlated with improved synaptic plasticity [127]. These observations suggest that PPARγ agonists prevent the impairment of synaptic plasticity by increasing BDNF expression and dendrite spine density.

Numerous studies have reported that kinases, such as CDK5, are also vital in the regulation of synaptic plasticity [154]. For example, a recent study showed that pioglitazone, via a proteasome-dependent manner, decreased the expression levels of p35 resulting in reduced CDK5 activity in neurons [154]. Moreover, blockage of CDK5 by pioglitazone prevented long-term potentiation (LTP) defects at CA3-CA1 synapses in APP/PS1 mice [155]. Alternatively, rosiglitazone was reported to induce an increase in the expression of neurotrophic factor-α1 (NF-α1), a neuroprotective protein, which increases prosurvival protein BCL 2 expression and provides neuroprotection in hippocampus [156]. Neurotrophins, such as nerve growth factor (NGF), can also induce PPARγ activation via the tyrosine kinase (TrkA) dependent signaling pathway and promote cell survival and differentiation [157]. PGC-1α gene therapy also increases NGF and exerts neuroprotective effects in AD mouse models [158]. These observations describe the significance of TZDs towards mitigating AD via improving mitochondrial function and synapse plasticity and reducing memory loss. Overall, PPARγ activation can simultaneously promote mitochondrial functions, improve metabolic and energy regulation, modulate neuroinflammation, stimulate axonal growth and myelination, and clear toxic Aβ from the brain [159].

5. PPAR Agonists

5.1. Conventional PPARγ Agonists: Drawbacks and Limitations

Rosiglitazone and pioglitazone have been recognized as potential treatments for the AD through their insulin sensitizing and anti-inflammatory effects [160]. Several clinical studies have tested the efficacy of TZDs treatments in AD [161]. However, some clinical trials utilizing pioglitazone have failed to show therapeutic benefit [162, 163]. A meta-analysis study showed insufficient evidence to support use of rosiglitazone in amnestic mild cognitive impairment and AD patients. Interestingly, pioglitazone showed efficacy especially in patients with comorbid diabetes mellitus [164]. However, another meta-analysis indicated that there is no statistically significant benefit with PPAR agonists in mild-to-moderate AD patients [165]. However, as previously stated, full agonists of PPARγ mediated closed conformation of the AF2 helix is responsible for many TZDs side effects [5254]. Some of the most common adverse effects noted with conventional PPAR agonists include edema and heart enlargement [35, 166]. Discovery and development of specific novel PPARγ ligands with improved therapeutic profiles provide a molecular framework for future developments of pharmacological PPARγ agonists with advantages over current TZDs drugs. Review of several clinical trials utilizing PPARγ agonists in the treatment of AD has been summarized in Table 1, with references and highlights of the study.

TitleTreatment# Of subjectsMethodsInclusion criteriaMajor outcome(s)Results of major outcome(s)Reference

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate ADRosi 2mg, Rosi 4mg, Rosi 8mg, or placebo daily for 24 weeks511RCTProbable AD, MMSE score of 16-26ADAS-Cog and CIBIC+No significant difference; exploratory analyses suggested that ApoE4 non-carriers exhibited cognitive improvement with 8mg dose of Rosi[35]

Rosiglitazone monotherapy in mild-to-moderate AD: results from a randomized, double-blind, placebo-controlled phase III study.Rosi XR 2mg, Rosi XR 8 mg, donepezil 10mg, or placebo daiy for 24 weeks693RCTProbable AD, MMSE score of 10-23ADAS-Cog and CIBIC+No significant difference for Rosi group vs. placebo; no interaction between treatment and ApoE status[36]

Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate AD: two phase 3 studies.Rosi XR 2mg, Rosi XR 8 mg, or placebo daily for 48 weeks in addition to an AChEI2,822RCTMild-moderate probable AD, MMSE score of 10-26ADAS-Cog and CDR-SBNo significant difference; no interaction between treatment and ApoE status[37]

Efficacy of PPAR- agonist pioglitazone in mild ADPio 15-30 mg daily or no treatment for 6 months42randomized, open-labelMild AD, Clinical Dementia Rating score of 0.5 or 1MMSE, ADAS-CogSignificant improvement in MMSE and ADAS-cog from baseline in pio treated subjects[38]

Biomarker Qualification for Risk of MCI Due to AD and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset (TOMMORROW)Pio 0.8mg SR daily or placebo for up to 5 years3,494RCTCognitively normal patientsTime to diagnosis of MCI due to AD for subjects in the high-risk stratumTrial discontinued due to inadequate treatment effect; full results not yet published[39]

Telmisartan vs. Perindopril in Hypertensive Mild-Moderate AD Patients (SARTAN-AD)Telmi 40mg, Telmi 80mg, perindopril 2mg, perindopril 4mg, or perindopril 8mg daily for 12 monthsgoal of 240Randomized, open labelProbable AD or possible AD dementia due to concomitant cerebrovascular disease, MMSE 16-27Ventricular enlargement, cognitive function based on ADAS-cog and cognitive batteryTrial is ongoing[40]

Effects of telmisartan on the level of A1-42, interleukin-1, TNF and cognition in hypertensive patients with ADTelmi 40-80mg or amlodipine 5-10 mg daily for 6 months48RandomizedProbable AD and essential hypertensionADAS-Cog and MMSESignificant improvement in MMSE and ADAS-cog in Telmi treated subjects compared to amlodipine treated subjects[41]

Phase 2a Feasibility Study of T3D-959 in Subjects with Mild to Moderate ADT3D-959 3mg, 10mg, 30mg, or 90mg once daily for 2 weeks36Randomized, open-labelMild-to-moderate AD, MMSE score of 14 -26FDG-PET Imaging, ADAS-CogTrends towards improvement in ADAS-Cog[42]

Clinical trials of PPARγ agonists. AChEI: acetylcholinesterase inhibitor; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s disease assessment scale cognitive subscale; ApoE: apolipoprotein E; CDR-SB: clinical dementia rating scale sum of boxes; CIBIC+: clinician’s interview-based impression of change with caregiver input; FDG-PET: fluorodeoxyglucose-positron emission tomography; MMSE: mini mental status exam; PPAR-γ: peroxisome proliferator activated receptor gamma; Pio: pioglitazone; Rosi: rosiglitazone; Telmi: telmisartan; *T3D-959 is a dual PPARδ/γ agonist.
5.2. New Direction for PPARγ Agonists: Development of Selective PPARγ Modulators (SPPARγMs)

Selective PPARγ modulators (SPPARγMs) have attracted considerable attention because of their ability to selectively target PPARγ activity states. Several investigators have characterized and identified promising SPPARγMs that serve as partial agonists for PPARγ in cell based transcriptional activity and adipogenic assays [167, 168]. SPPARγMs specifically bind to the LBD of PPARγ via an activation function 2 motif (AF2). This offers greater flexibility in response to diverse ligands, resulting in different receptor conformations and coactivator and/or corepressor recruitment in different tissues [169]. Several SPPARγMs in preclinical studies have demonstrated strong insulin sensitizing activity in diet induced obese C57/BL6 mice with attenuated adverse effects on adiposity, weight gain, and cardiac related complications compared to potent full PPARγ agonists [170]. To further explain, the mechanism by which SPPARγMs uniquely interact with the receptor results in diminished conformational stability of the receptor when compared to traditional TZDs. Co-crystallography studies of the PPARγ LBD complexed with full PPARγ agonist rosiglitazone demonstrated strong hydrogen bonding with the Tyr473 site in helix 12 of the human PPARγ LBD. In contrast, rational drug design utilizing molecular modeling and crystallography structure analysis performed on the PPARγ LBD with SPPARγMs revealed that these compounds have the inability to form hydrogen bonding with Tyr473 due to the bonding distance with the carboxylic acid moiety [171, 172]. Findings from NMR studies have indicated that SPPARγMs induce a less stable confirmation than full PPARγ agonists (Figure 5) [173]. In addition, the Tyr473 site, within the helix 12 transcriptional activation function 2 domain, is involved in activation of the transcriptional coactivator binding pocket of the LBD [174]. Alteration of this site leads to the potential inability to directly stabilize this region and may serve as the physical basis for the differential receptor coactivator interaction, altered transcriptional activity, and reduced deleterious effects upon the heart and body associated with current full PPARγ agonists. Traditional PPARγ agonists, which display strong interaction with Tyr473, displace the inhibitory cofactors NCoR/SMRT and recruit P300/CBP, which confirms the most stable confirmation of the ligand binding pocket. These cofactors serve as histone acetylators and thus conform the receptor to the adipogenic gene in a stable confirmation. SPPARγMs that lack interaction with Tyr473 induce less stable confirmation and thus allow predictions for alternative cofactor associations with the receptor including PGC-1α. The potential of SPPARγMs in AD is just beginning and will likely lead to development of therapeutic targets for mitigating AD. Tyr473 in the AF2 region of the LBD has been shown to be a critical site of interaction between the full agonists and the PPARγ receptor. Studies on mutant PPARγ-LBD, where Tyr473 is replaced with alanine, revealed that interaction with Tyr473 is necessary for full agonist activity [175]. To this, various SPPARγMs such as SPPARγM2, GW0072, INT131, and PA082 have been observed not to interact with Tyr473 residue. Recently, Bruning and coworkers demonstrated that several SPPARγMs (BVT13, nTZDpa, MRL-20, MRL-24, SR145, and SR147) cause activation of PPARγ by interaction and stabilization of the β-sheet and H3 rather than AF2 helix of the LBD, which acts as a novel coactivator interaction site [176]. It suggests that the structurally diverse SPPARγMs, due to their distinct physical interaction with the receptor, uniquely bind to the receptor, resulting in diminished conformational stability compared with full agonists. Figure 5 illustrates the conformational changes in PPARγ/RXR receptor induced by the binding of full agonists or SPPARγMs, leading to coregulator heterodimer dissociation/recruitment, which forms the molecular basis for selective gene regulation that triggers specific metabolic effects. Studies with several SPPARγMs have mainly focused on four families of coregulators: NCoR and silencing mediator for retinoid and thyroid hormone receptors (SMRT), the p300 and CREB binding protein (CBP) family, the PPARγ coactivator 1 (PGC-1) family, and the p160 family, which are composed of three related coactivators (SRC1/NCoA1, GRIP1/TIF2/SRC2, and pCIP/RAC3/ACTR/AIB1/TRAM1/SRC3). Corepressors NCoR and Not1 and SMRT are known to downregulate full PPARγ agonist-mediated transcriptional activity and inhibit adipogenesis [177]. Several SPPARγMs that induce selective PPARγ or lack displacement of corepressors have been observed to display partial or antagonistic effects on adipogenesis and yet maintained insulin sensitization. For example, telmisartan and halofenate, which act as a SPPARγMs, induce reduced dissociation of corepressors and thus are partially adipogenic, while GW0072 (PPARγ repressor) does not dissociate corepressors resulting in preventing adipogenesis. However, they all are effective insulin sensitizers. Alternatively, FK614 causes NCoR dissociation equal to that of rosiglitazone and is a full agonist in adipogenesis assay, but shows several characteristics of SPPARγM in vivo [173]. Since the corepressor dissociation studies with SPPARγMs are limited and given that SPPARγMs display diverse activity in adipogenesis assay, their effects on AD needs to be further explored with respect to corepressor interaction and its role in PPARγ-mediated insulin sensitization. Coactivators CBP/p300, TIF2 and SRC-3 seem to favor fat accumulation [178], and therefore their recruitment may not be desirable, while the physiological role of other coactivators, such as SRC1 and PGC-1α, is more associated with energy regulation. Thus, the specific recruitment of TIF2 over SRC1 may be a reason for lipid accumulation observed following rosiglitazone treatment in diabetic patients [179]. Interestingly, MBX-102, a SPPARγM, promotes higher recruitment of CBP, TIF2, SRC1, and PGC-1α when compared to a full agonist [173]. Other SPPARγMs including FMOC-leucine, PA-082, GW0072, and FK614 favor the recruitment of PGC-1α over that of SRC-1, TIF2, or p300 when compared with rosiglitazone [60, 180]. The role of PGC-1α is important for PPARγ activity as it acts as a docking surface for integrating the actions of transcription factors and cofactors for regulation of mitochondrial biogenesis and oxidative capacity [181]. Also, it has been shown that rosiglitazone upregulates the constitutively low expression of PGC-1α in white adipose tissue [182]. In the aged brain, PGC-1α regulates the expression of sirtuin 3, which is a factor related to the aging process [183]. It has been observed that brains from patients with neurodegenerative diseases display low levels of PGC-1α which leads to mitochondrial dysfunction and oxidative stress [184]. PGC-1α regulates mitochondrial density in neurons and PGC-1α–knockout mice showed an increased sensitivity to the degeneration of dopaminergic and glutamatergic neurons in the brain [185]. Moreover, alternative studies have demonstrated that the reduction of mitochondrial gene expression in PGC-1α–knockout mice leads to neuronal dysfunction [186]. Given that PGC-1α plays a crucial role in neuronal function and regulates mitochondrial function, PGC-1α could ameliorate mitochondrial dysfunction and improve cognitive function in AD [118, 187]. Therefore, SPPARγMs favoring the recruitment of PGC-1α may lead to the discovery of new drug therapy for AD. Some of the newer PPARγ agonists in several disease models are listed in Table 2, with references and highlights of the study.

LigandClassificationModelAmyloid Other pathologiesreferences

NP00111 and NP01138   
(Novel TZDs)
PPARγ agonistcerebral cortex of embryonic day 18 ratsDecreased AβPrevented activation of microglia and suppressed inflammatory markers.
Restricted cortical or hippocampal neuronal cell death

Pirinixic acid derivate MH84Dual gamma-secretase/PPARγ modulatorThy-1 Aβ micereduced cerebral levels of Aβ40NA[44]

INT131SPPARMs- non-thiazolidinedione compoundRat primary hippocampal neuronsImproved neuronal survival against Aβincreased dendritic branching, improved mitochondrial functions[45]

T3D-959Dual PPAR-δ/PPARγ agoniststreptozotocin-induced AD mouse modelreduced AβReduced levels of oxidative stress, normalized expression of phospho-tau and choline acetyltransferase. [42]
Intracerebral streptozotocin (i.c. STZ) model-NA-Improved Brain Insulin/IGF Signaling and reduced neuroinflammation [46]

PPARγ agonists in various models of AD and its effects on various pathologies. Amyloid beta (Aβ), peroxisome proliferator-activated receptor gamma (PPAR-γ), thiazolidinediones (TZDs), streptozotocin (STZ).

6. Conclusions and Future Directions

Following the utilization of PPARγ agonists for type 2 diabetes mellitus in improving insulin sensitivity, the pleiotropic effects of PPARγ in neurodegenerative diseases like AD have been increasingly investigated in recent years. Extensive research undertaken to improve the efficacy and/or safety of first-generation PPARγ agonists (the TZDs) has led to a greater understanding of the complexity of PPAR regulation, specifically the importance of coactivator and corepressor proteins. Developing novel agonists that exploit cofactor biology to derive better agents and reduce the unwanted deleterious effects is currently in process. Recent efforts to demonstrate differential cofactor recruitment and to develop better preclinical efficacy/safety profiles of SPPARγMs compared to conventional PPARγ agonists are underway. Future directions in PPAR research are likely to focus on optimizing the PPAR subtype interaction profile, maximizing inhibition of PPARγ phosphorylation, and screening against off-target activity.


There was no involvement of anyone other than the authors who (1) has an interest in the outcome of the work, (2) is affiliated to an organization with such an interest, or (3) was employed or paid by a funder, in the commissioning, conception, planning, design, conduct, or analysis of the work, the preparation or editing of the manuscript, or the decision to publish.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.


The current study was supported by funding to Drs. Amin and Suppiramaniam, NIHR15AG048643.


  1. Alzheimer’s Association, “2018 Alzheimers disease facts and figures,” Alzheimer’s & Dementia, vol. 14, no. 3, pp. 367–429, 2018, http://linkinghub.elsevier.com/retrieve/pii/S1552526018300414. View at: Publisher Site | Google Scholar
  2. B. Chami, A. J. Steel, S. M. De La Monte, and G. T. Sutherland, “The rise and fall of insulin signaling in Alzheimer’s disease,” Metabolic Brain Disease, vol. 31, no. 3, pp. 497–515, 2016, http://www.ncbi.nlm.nih.gov/pubmed/26883429. View at: Publisher Site | Google Scholar
  3. S. M. de la Monte, M. Tong, N. Lester-Coll, M. Plater Jr, and J. R. Wands, “Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 89–109, 2006, http://www.ncbi.nlm.nih.gov/pubmed/16988486. View at: Publisher Site | Google Scholar
  4. A. Ott, R. P. Stolk, F. van Harskamp, H. A. P. Pols, A. Hofman, and M. M. B. Breteler, “Diabetes mellitus and the risk of dementia: the Rotterdam Study,” Neurology, vol. 53, no. 9, pp. 1937–1942, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10599761. View at: Publisher Site | Google Scholar
  5. E. Recio-Pinto, F. F. Lang, and D. N. Ishii, “Insulin and insulin-like growth factor II permit nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 81, no. 8, pp. 2562–2566, 1984, http://www.ncbi.nlm.nih.gov/pubmed/6326132. View at: Publisher Site | Google Scholar
  6. H. Sancheti, G. Akopian, F. Yin et al., “Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of alzheimer’s disease,” PLoS ONE, vol. 8, no. 7, p. e69830, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23875003. View at: Publisher Site | Google Scholar
  7. W. A. Pedersen, P. J. McMillan, J. J. Kulstad, J. B. Leverenz, S. Craft, and G. R. Haynatzki, “Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice,” Experimental Neurology, vol. 199, no. 2, pp. 265–273, 2006, http://www.ncbi.nlm.nih.gov/pubmed/16515786. View at: Publisher Site | Google Scholar
  8. L. Escribano, A.-M. Simón, E. Gimeno et al., “Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology,” Neuropsychopharmacology, vol. 35, no. 7, pp. 1593–1604, 2010, http://www.ncbi.nlm.nih.gov/pubmed/20336061. View at: Publisher Site | Google Scholar
  9. H. Cheng, Y. Shang, L. Jiang et al., “The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis,” International Journal of Neuroscience, vol. 126, no. 4, pp. 299–307, 2015, http://www.tandfonline.com/doi/full/10.3109/00207454.2015.1015722. View at: Publisher Site | Google Scholar
  10. F. Masciopinto, N. Di Pietro, C. Corona et al., “Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD and wild-type mice,” Cell Death & Disease, vol. 3, no. 12, pp. e448–e448, 2012, http://www.ncbi.nlm.nih.gov/pubmed/23254291. View at: Publisher Site | Google Scholar
  11. L.-Y. Jiang, S.-S. Tang, X.-Y. Wang et al., “PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes mellitus,” CNS Neuroscience & Therapeutics, vol. 18, no. 8, pp. 659–666, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22620268. View at: Publisher Site | Google Scholar
  12. G. Landreth, Q. Jiang, S. Mandrekar, and M. Heneka, “PPARγ agonists as therapeutics for the treatment of Alzheimer's disease,” Neurotherapeutics, vol. 5, no. 3, pp. 481–489, 2008, http://www.ncbi.nlm.nih.gov/pubmed/18625459. View at: Publisher Site | Google Scholar
  13. A. Kermani and A. Garg, “Thiazolidinedione-Associated Congestive Heart Failure and Pulmonary Edema,” Mayo Clinic Proceedings, vol. 78, no. 9, pp. 1088–1091, 2003, http://www.ncbi.nlm.nih.gov/pubmed/12962163. View at: Publisher Site | Google Scholar
  14. L. Nagy and J. W. R. Schwabe, “Mechanism of the nuclear receptor molecular switch,” Trends in Biochemical Sciences, vol. 29, no. 6, pp. 317–324, 2004, http://www.ncbi.nlm.nih.gov/pubmed/15276186. View at: Publisher Site | Google Scholar
  15. J. C. Corton, S. P. Anderson, and A. Stauber, “Central role of peroxisome proliferator–activated receptors in the actions of peroxisome proliferators,” Annual Review of Pharmacology and Toxicology, vol. 40, no. 1, pp. 491–518, 2000, http://www.ncbi.nlm.nih.gov/pubmed/10836145. View at: Publisher Site | Google Scholar
  16. S. Neschen, K. Morino, J. Dong et al., “n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha–Dependent manner,” Diabetes, vol. 56, no. 4, pp. 1034–1041, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17251275. View at: Publisher Site | Google Scholar
  17. R. C. Scarpulla, R. B. Vega, and D. P. Kelly, “Transcriptional integration of mitochondrial biogenesis,” Trends in Endocrinology & Metabolism, vol. 23, no. 9, pp. 459–466, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22817841. View at: Publisher Site | Google Scholar
  18. Y. Zhu, C. Qi, J. R. Korenberg et al., “Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 92, no. 17, pp. 7921–7925, 1995, http://www.ncbi.nlm.nih.gov/pubmed/7644514. View at: Publisher Site | Google Scholar
  19. G. Medina-Gomez, S. L. Gray, L. Yetukuri et al., “PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism,” PLoS Genetics, vol. 3, no. 4, p. e64, 2007, http://dx.plos.org/10.1371/journal.pgen.0030064. View at: Publisher Site | Google Scholar
  20. M. T. Heneka and G. E. Landreth, “PPARs in the brain,” Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, vol. 1771, no. 8, pp. 1031–1045, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17569578. View at: Publisher Site | Google Scholar
  21. S. Moreno, S. Farioli-Vecchioli, and M. P. Cerù, “Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS,” Neuroscience, vol. 123, no. 1, pp. 131–145, 2004, http://www.ncbi.nlm.nih.gov/pubmed/14667448. View at: Publisher Site | Google Scholar
  22. K. Murakami, K. Tobe, T. Ide et al., “A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-α (PPAR-α) and PPAR-γ. Effect of PPAR-α activation on abnormal lipid metabolism in liver of Zucker fatty rats,” Diabetes, vol. 47, no. 12, pp. 1841–1847, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9836514. View at: Publisher Site | Google Scholar
  23. I. Saluja, J. G. Granneman, and R. P. Skoff, “PPAR delta agonists stimulate oligodendrocyte differentiation in tissue culture,” Glia, vol. 33, no. 3, pp. 191–204, 2001, http://www.ncbi.nlm.nih.gov/pubmed/11241737. View at: Publisher Site | Google Scholar
  24. P. E. Polak, S. Kalinin, C. Dello Russo et al., “Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 168, no. 1-2, pp. 65–75, 2005, http://www.ncbi.nlm.nih.gov/pubmed/16098614. View at: Publisher Site | Google Scholar
  25. P. D. Storer, J. Xu, J. Chavis, and P. D. Drew, “Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis,” Journal of Neuroimmunology, vol. 161, no. 1-2, pp. 113–122, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15748950. View at: Publisher Site | Google Scholar
  26. B. Desvergne and W. Wahli, “Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10529898. View at: Publisher Site | Google Scholar
  27. J.-D. Lin, C. Handschin, and B. M. Spiegelman, “Metabolic control through the PGC-1 family of transcription coactivators,” Cell Metabolism, vol. 1, no. 6, pp. 361–370, 2005, https://www.sciencedirect.com/science/article/pii/S1550413105001427. View at: Publisher Site | Google Scholar
  28. M. P. Mattson, “Energy intake and exercise as determinants of brain health and vulnerability to injury and disease,” Cell Metabolism, vol. 16, no. 6, pp. 706–722, 2012, http://www.ncbi.nlm.nih.gov/pubmed/23168220. View at: Publisher Site | Google Scholar
  29. D. Li, K. Chen, N. Sinha et al., “The effects of PPAR-γ ligand pioglitazone on platelet aggregation and arterial thrombus formation,” Cardiovascular Research, vol. 65, no. 4, pp. 907–912, 2005, https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2004.11.027. View at: Publisher Site | Google Scholar
  30. E. Burgermeister and R. Seger, “MAPK kinases as nucleo-cytoplasmic shuttles for PPARγ,” Cell Cycle, vol. 6, no. 13, pp. 1539–1548, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17611413. View at: Publisher Site | Google Scholar
  31. M. Luconi, G. Cantini, and M. Serio, “Peroxisome proliferator-activated receptor gamma (PPARγ): is the genomic activity the only answer?” Steroids, vol. 75, no. 8-9, pp. 585–594, 2010, http://www.ncbi.nlm.nih.gov/pubmed/19900469. View at: Publisher Site | Google Scholar
  32. H. S. Camp and S. R. Tafuri, “Regulation of Peroxisome Proliferator-activated Receptor γ Activity by Mitogen-activated Protein Kinase,” The Journal of Biological Chemistry, vol. 272, no. 16, pp. 10811–10816, 1997, http://www.ncbi.nlm.nih.gov/pubmed/9099735. View at: Publisher Site | Google Scholar
  33. E. Hu, J. B. Kim, P. Sarraf, and B. M. Spiegelman, “Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ,” Science, vol. 274, no. 5295, pp. 2100–2103, 1996, http://www.ncbi.nlm.nih.gov/pubmed/8953045. View at: Publisher Site | Google Scholar
  34. J. H. Choi, A. S. Banks, J. L. Estall et al., “Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ 3 by Cdk5,” Nature, vol. 466, no. 7305, pp. 451–456, 2010, http://www.ncbi.nlm.nih.gov/pubmed/20651683. View at: Publisher Site | Google Scholar
  35. M. E. Risner, A. M. Saunders, J. F. B. Altman et al., “Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease,” The Pharmacogenomics Journal, vol. 6, no. 4, pp. 246–254, 2006, http://www.ncbi.nlm.nih.gov/pubmed/16446752. View at: Publisher Site | Google Scholar
  36. M. Gold, C. Alderton, M. Zvartau-Hind et al., “Rosiglitazone monotherapy in mild-to-moderate alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study,” Dementia and Geriatric Cognitive Disorders, vol. 30, no. 2, pp. 131–146, 2010, http://www.ncbi.nlm.nih.gov/pubmed/20733306. View at: Publisher Site | Google Scholar
  37. C. Harrington, S. Sawchak, C. Chiang et al., “Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies,” Current Alzheimer Research, vol. 8, no. 5, pp. 592–606, 2011, http://www.ncbi.nlm.nih.gov/pubmed/21592048. View at: Publisher Site | Google Scholar
  38. T. Sato, H. Hanyu, K. Hirao, H. Kanetaka, H. Sakurai, and T. Iwamoto, “Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease,” Neurobiology of Aging, vol. 32, no. 9, pp. 1626–1633, 2011, http://www.ncbi.nlm.nih.gov/pubmed/19923038. View at: Publisher Site | Google Scholar
  39. Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer’s Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset - Tabular View, https://clinicaltrials.gov/ct2/show/record/NCT01931566?view=record.
  40. Telmisartan vs. Perindopril in Hypertensive Mild-Moderate Alzheimer’s Disease Patients - Tabular View - ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/record/NCT02085265.
  41. W. Li, J. Zhang, F. Lu, M. Ma, J. Wang, and A. Suo, “Effects of telmisartan on the level of Aβ1-42, interleukin-1β, tumor necrosis factor α and cognition in hypertensive patients with Alzheimer’s disease,” Zhonghua Yi Xue Za Zhi, vol. 92, no. 39, pp. 2743–2746, 2012, http://www.ncbi.nlm.nih.gov/pubmed/23290159. View at: Google Scholar
  42. M. Tong, C. Deochand, J. Didsbury, and S. M. de la Monte, “T3D-959: A Multi-Faceted Disease Remedial Drug Candidate for the Treatment of Alzheimer’s Disease,” Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 123–138, 2016, http://www.ncbi.nlm.nih.gov/pubmed/26836193. View at: Publisher Site | Google Scholar
  43. R. Luna-Medina, M. Cortes-Canteli, M. Alonso, A. Santos, A. Martínez, and A. Perez-Castillo, “Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation,” The Journal of Biological Chemistry, vol. 280, no. 22, pp. 21453–21462, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15817469. View at: Publisher Site | Google Scholar
  44. M. Pohland, M. Pellowska, H. Asseburg et al., “MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer’s disease,” Alzheimer's Research & Therapy, vol. 10, no. 1, p. 18, 2018, http://www.ncbi.nlm.nih.gov/pubmed/29433569. View at: Publisher Site | Google Scholar
  45. J. A. Godoy, J. M. Zolezzi, and N. C. Inestrosa, “INT131 increases dendritic arborization and protects against Aβ toxicity by inducing mitochondrial changes in hippocampal neurons,” Biochemical and Biophysical Research Communications, vol. 490, no. 3, pp. 955–962, 2017, http://www.ncbi.nlm.nih.gov/pubmed/28655613. View at: Publisher Site | Google Scholar
  46. S. M. de la Monte, M. Tong, I. Schiano, and J. Didsbury, “Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer’s Disease,” Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 849–864, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27802237. View at: Publisher Site | Google Scholar
  47. D. Moras and H. Gronemeyer, “The nuclear receptor ligand-binding domain: structure and function,” Current Opinion in Cell Biology, vol. 10, no. 3, pp. 384–391, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9640540. View at: Publisher Site | Google Scholar
  48. B. A. Johnson, E. M. Wilson, Y. Li, D. E. Moller, R. G. Smith, and G. Zhou, “Ligand-induced stabilization of PPARγ monitored by NMR spectroscopy: implications for nuclear receptor activation,” Journal of Molecular Biology, vol. 298, no. 2, pp. 187–194, 2000, http://www.ncbi.nlm.nih.gov/pubmed/10764590. View at: Publisher Site | Google Scholar
  49. T. S. Hughes, M. J. Chalmers, S. Novick et al., “Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism,” Structure, vol. 20, no. 1, pp. 139–150, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22244763. View at: Publisher Site | Google Scholar
  50. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ,” Nature, vol. 395, no. 6698, pp. 137–143, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9744270. View at: Publisher Site | Google Scholar
  51. R. T. Gampe, V. G. Montana, M. H. Lambert et al., “Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors,” Molecular Cell, vol. 5, no. 3, pp. 545–555, 2000, http://www.ncbi.nlm.nih.gov/pubmed/10882139. View at: Publisher Site | Google Scholar
  52. U. Grether, W. Klaus, B. Kuhn, H. P. Maerki, P. Mohr, and M. B. Wright, “New insights on the mechanism of PPAR-targeted drugs,” ChemMedChem, vol. 5, no. 12, pp. 1973–1976, 2010, http://doi.wiley.com/10.1002/cmdc.201000446. View at: Publisher Site | Google Scholar
  53. L. Guasch, E. Sala, C. Valls et al., “Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity,” Journal of Computer-Aided Molecular Design, vol. 25, no. 8, pp. 717–728, 2011, http://www.ncbi.nlm.nih.gov/pubmed/21691811. View at: Publisher Site | Google Scholar
  54. T. S. Hughes, P. K. Giri, I. M. de Vera et al., “An alternate binding site for PPARγ ligands,” Nature Communications, vol. 5, no. 1, 2014, http://www.nature.com/articles/ncomms4571. View at: Publisher Site | Google Scholar
  55. M. B. Wright, M. Bortolini, M. Tadayyon, and M. Bopst, “Minireview: challenges and opportunities in development of PPAR agonists,” Molecular Endocrinology, vol. 28, no. 11, pp. 1756–1768, 2014, http://www.ncbi.nlm.nih.gov/pubmed/25148456. View at: Publisher Site | Google Scholar
  56. S. Garcia-Vallvé, L. Guasch, S. Tomas-Hernández et al., “Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage,” Journal of Medicinal Chemistry, vol. 58, no. 14, pp. 5381–5394, 2015, http://pubs.acs.org/doi/10.1021/jm501155f. View at: Publisher Site | Google Scholar
  57. M. Ahmadian, J. M. Suh, N. Hah et al., “PPARγ signaling and metabolism: the good, the bad and the future,” Nature Medicine, vol. 99, no. 5, pp. 557–566, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23652116. View at: Publisher Site | Google Scholar
  58. C. Pirat, A. Farce, N. Lebègue et al., “Targeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of Modulators,” Journal of Medicinal Chemistry, vol. 55, no. 9, pp. 4027–4061, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22260081. View at: Publisher Site | Google Scholar
  59. G. Pochetti, C. Godio, N. Mitro et al., “Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor γ ligand-binding domain in the complex with two enantiomeric ligands,” The Journal of Biological Chemistry, vol. 282, no. 23, pp. 17314–17324, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17403688. View at: Publisher Site | Google Scholar
  60. F. Zhang, B. E. Lavan, and F. M. Gregoire, “Selective Modulators of PPAR-γ Activity: Molecular Aspects Related to Obesity and Side-Effects,” PPAR Research, Article ID 32696, pp. 1–7, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17389769. View at: Publisher Site | Google Scholar
  61. W. Zheng, X. Feng, L. Qiu et al., “Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes,” Diabetologia, vol. 56, no. 2, pp. 401–411, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23178929. View at: Publisher Site | Google Scholar
  62. A. Kumar, A. Singh, and Ekavali, “A review on Alzheimer's disease pathophysiology and its management: an update,” Pharmacological Reports, vol. 67, no. 2, pp. 195–203, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25712639. View at: Publisher Site | Google Scholar
  63. M. R. Bronzuoli, A. Iacomino, L. Steardo, and C. Scuderi, “Targeting neuroinflammation in Alzheimer’s disease,” Journal of Inflammation Research, vol. 9, pp. 199–208, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27843334. View at: Publisher Site | Google Scholar
  64. I. G. Onyango, J. Dennis, and S. M. Khan, “Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies,” Aging and Disease (A&D), vol. 7, no. 2, pp. 201–214, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27114851. View at: Publisher Site | Google Scholar
  65. S. T. Ferreira, J. R. Clarke, T. R. Bomfim, and F. G. de Felice, “Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease,” Alzheimer’s & Dementia, vol. 10, no. 1, pp. S76–S83, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24529528. View at: Publisher Site | Google Scholar
  66. M. Sheng, B. L. Sabatini, and T. C. Südhof, “Synapses and Alzheimer’s disease,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 5, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22491782. View at: Google Scholar
  67. J-C. Lambert, C. A. Ibrahim-Verbaas, D. Harold, A. C. Naj, R. Sims, C. Bellenguez et al., “Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease,” Nature Genetics, vol. 45, no. 12, pp. 1452–1458, 2013, http://www.ncbi.nlm.nih.gov/pubmed/24162737. View at: Google Scholar
  68. L. Bertram, M. B. McQueen, K. Mullin, D. Blacker, and R. E. Tanzi, “Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database,” Nature Genetics, vol. 39, no. 1, pp. 17–23, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17192785. View at: Publisher Site | Google Scholar
  69. A. Payton, P. Sindrewicz, V. Pessoa et al., “A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging,” Neurobiology of Aging, vol. 39, pp. 217.e1–217.e7, 2016, http://www.ncbi.nlm.nih.gov/pubmed/26742953. View at: Publisher Site | Google Scholar
  70. W. K. Gottschalk and M. Mihovilovic, “The Role of Upregulated APOE in Alzheimer's Disease Etiology,” Journal of Alzheimer's Disease & Parkinsonism, vol. 6, no. 1, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27104063. View at: Publisher Site | Google Scholar
  71. C. Linnertz, L. Anderson, W. Gottschalk et al., “The cis-regulatory effect of an Alzheimer’s disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes,” Alzheimer's & Dementia, vol. 10, no. 5, pp. 541–551, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24439168. View at: Publisher Site | Google Scholar
  72. S. Subramanian, W. K. Gottschalk, S. Y. Kim, A. D. Roses, and O. Chiba-Falek, “The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1863, no. 3, pp. 810–816, 2017, https://www.sciencedirect.com/science/article/pii/S092544391730008X. View at: Publisher Site | Google Scholar
  73. J. Barrera, S. Subramanian, O. Chiba-Falek, and J. Fuh, “Probing the role of PPARγ in the regulation of late-onset Alzheimer’s disease-associated genes,” PLoS ONE, vol. 13, no. 5, p. e0196943, 2018, http://dx.plos.org/10.1371/journal.pone.0196943. View at: Publisher Site | Google Scholar
  74. S. H. Barage and K. D. Sonawane, “Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer's disease,” Neuropeptides, vol. 52, pp. 1–18, 2015, http://www.ncbi.nlm.nih.gov/pubmed/26149638. View at: Publisher Site | Google Scholar
  75. M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek et al., “Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1-42 levels in APPV717I transgenic mice,” Brain, vol. 128, no. 6, pp. 1442–1453, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15817521. View at: Publisher Site | Google Scholar
  76. S. Mandrekar-Colucci, J. C. Karlo, and G. E. Landreth, “Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease,” The Journal of Neuroscience, vol. 32, no. 30, pp. 10117–10128, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22836247. View at: Publisher Site | Google Scholar
  77. M. Shibata, S. Yamada, S. R. Kumar et al., “Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier,” The Journal of Clinical Investigation, vol. 106, no. 12, pp. 1489–1499, 2000, http://www.ncbi.nlm.nih.gov/pubmed/11120756. View at: Publisher Site | Google Scholar
  78. R. Deane, Z. Wu, A. Sagare et al., “LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms,” Neuron, vol. 43, no. 3, pp. 333–344, 2004, http://www.ncbi.nlm.nih.gov/pubmed/15294142. View at: Publisher Site | Google Scholar
  79. A. P. Lillis, L. B. Van Duyn, J. E. Murphy-Ullrich, and D. K. Strickland, “LDL receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies,” Physiological Reviews, vol. 88, no. 3, pp. 887–918, 2008, http://www.ncbi.nlm.nih.gov/pubmed/18626063. View at: Publisher Site | Google Scholar
  80. A. Ramanathan, A. R. Nelson, A. P. Sagare, and B. V. Zlokovic, “Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1,” Frontiers in Aging Neuroscience, vol. 7, 2015, http://www.ncbi.nlm.nih.gov/pubmed/26236233. View at: Publisher Site | Google Scholar
  81. A. Gauthier, G. Vassiliou, F. Benoist, and R. McPherson, “Adipocyte Low Density Lipoprotein Receptor-related Protein Gene Expression and Function Is Regulated by Peroxisome Proliferator-activated Receptor γ,” The Journal of Biological Chemistry, vol. 278, no. 14, pp. 11945–11953, 2003, http://www.ncbi.nlm.nih.gov/pubmed/12551936. View at: Publisher Site | Google Scholar
  82. A. N. Rondón-Ortiz, C. L. Lino Cardenas, J. Martínez-Málaga et al., “High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells,” Frontiers in Pharmacology, vol. 8, p. 772, 2017, http://www.ncbi.nlm.nih.gov/pubmed/29201005. View at: Publisher Site | Google Scholar
  83. J. H. Moon, H. J. Kim, H. M. Kim et al., “Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia,” Molecular Endocrinology, vol. 49, no. 3, pp. 165–174, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22889684. View at: Publisher Site | Google Scholar
  84. Q. Jiang, C. Y. D. Lee, S. Mandrekar et al., “ApoE promotes the proteolytic degradation of Aβ,” Neuron, vol. 58, no. 5, pp. 681–693, 2008, http://www.ncbi.nlm.nih.gov/pubmed/18549781. View at: Publisher Site | Google Scholar
  85. M. Yamanaka, T. Ishikawa, A. Griep, D. Axt, M. P. Kummer, and M. T. Heneka, “PPARγ/RXRA-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice,” The Journal of Neuroscience, vol. 32, no. 48, pp. 17321–17331, 2012, http://www.ncbi.nlm.nih.gov/pubmed/23197723. View at: Publisher Site | Google Scholar
  86. L. A. Medeiros, T. Khan, J. B. El Khoury et al., “Fibrillar Amyloid Protein Present in Atheroma Activates CD36 Signal Transduction,” The Journal of Biological Chemistry, vol. 279, no. 11, pp. 10643–10648, 2004. View at: Publisher Site | Google Scholar
  87. P. F. Chapman, G. L. White, M. W. Jones et al., “Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice,” Nature Neuroscience, vol. 2, no. 3, pp. 271–276, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10195221. View at: Publisher Site | Google Scholar
  88. K. Hsiao, P. Chapman, S. Nilsen et al., “Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice,” Science, vol. 274, no. 5284, pp. 99–102, 1996, http://www.ncbi.nlm.nih.gov/pubmed/8810256. View at: Publisher Site | Google Scholar
  89. K. Johnson-Wood, M. Lee, R. Motter et al., “Amyloid precursor protein processing and A 42 deposition in a transgenic mouse model of Alzheimer disease,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 94, no. 4, pp. 1550–1555, 1997, http://www.ncbi.nlm.nih.gov/pubmed/9037091. View at: Publisher Site | Google Scholar
  90. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9422509. View at: Publisher Site | Google Scholar
  91. M. Ricote, J. Huang, L. Fajas et al., “Expression of the peroxisome proliferator-activated receptor γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 95, no. 13, pp. 7614–7619, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9636198. View at: Publisher Site | Google Scholar
  92. C. Zhang, Y. Wang, D. Wang, J. Zhang, and F. Zhang, “NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies,” Frontiers in Aging Neuroscience, vol. 10, p. 83, 2018. View at: Publisher Site | Google Scholar
  93. A. C. Puhl, F. A. Milton, A. Cvoro et al., “Mechanisms of Peroxisome Proliferator Activated Receptor γ Regulation by Non-steroidal Anti-inflammatory Drugs,” Nuclear Receptor Signaling, vol. 13, no. 1, 2018, http://www.ncbi.nlm.nih.gov/pubmed/26445566. View at: Publisher Site | Google Scholar
  94. Y. Kitamura, S. Shimohama, H. Koike et al., “Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains,” Biochemical and Biophysical Research Communications, vol. 254, no. 3, pp. 582–586, 1999, http://www.ncbi.nlm.nih.gov/pubmed/9920782. View at: Publisher Site | Google Scholar
  95. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at: Publisher Site | Google Scholar
  96. R. Kapadia, J.-H. Yi, and R. Vemuganti, “Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists,” Frontiers in Bioscience, vol. 13, no. 5, pp. 1813–1826, 2008, http://www.ncbi.nlm.nih.gov/pubmed/17981670. View at: Publisher Site | Google Scholar
  97. M. T. Heneka, T. Klockgether, and D. L. Feinstein, “Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo,” The Journal of Neuroscience, vol. 20, no. 18, pp. 6862–6867, 2000, http://www.ncbi.nlm.nih.gov/pubmed/10995830. View at: Publisher Site | Google Scholar
  98. S. Lenglet, F. Montecucco, and F. Mach, “Role of Matrix Metalloproteinases in Animal Models of Ischemic Stroke,” Current Vascular Pharmacology, vol. 13, no. 2, pp. 161–166, 2015, https://www.ingentaconnect.com/content/ben/cvp/2015/00000013/00000002/art00005. View at: Publisher Site | Google Scholar
  99. C. K. Combs, D. E. Johnson, J. C. Karlo, S. B. Cannady, and G. E. Landreth, “Inflammatory Mechanisms in Alzheimer's Disease: Inhibition of β-Amyloid-Stimulated Proinflammatory Responses and Neurotoxicity by PPARγ Agonists,” The Journal of Neuroscience, vol. 20, no. 2, pp. 558–567, 2000, http://www.ncbi.nlm.nih.gov/pubmed/10632585. View at: Publisher Site | Google Scholar
  100. N. Nicolakakis, T. Aboulkassim, B. Ongali et al., “Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor γ agonist,” The Journal of Neuroscience, vol. 28, no. 37, pp. 9287–9296, 2008, http://www.ncbi.nlm.nih.gov/pubmed/18784309. View at: Publisher Site | Google Scholar
  101. E. M. Toledo and N. C. Inestrosa, “Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease,” Molecular Psychiatry, vol. 15, no. 3, pp. 272–285, 2010, http://www.ncbi.nlm.nih.gov/pubmed/19621015. View at: Publisher Site | Google Scholar
  102. M. E. Calhoun, P. Burgermeister, A. L. Phinney et al., “Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 96, no. 24, pp. 14088–14093, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10570203. View at: Publisher Site | Google Scholar
  103. E. Utreras, R. Hamada, M. Prochazkova et al., “Suppression of neuroinflammation in forebrain-specific Cdk5 conditional knockout mice by PPARγ agonist improves neuronal loss and early lethality,” Journal of Neuroinflammation, vol. 11, no. 1, p. 28, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24495352. View at: Publisher Site | Google Scholar
  104. J. P. Lopes, C. R. Oliveira, and P. Agostinho, “Neurodegeneration in an Aβ-induced model of Alzheimer's disease: The role of Cdk5,” Aging Cell, vol. 9, no. 1, pp. 64–77, 2010, http://www.ncbi.nlm.nih.gov/pubmed/19895631. View at: Publisher Site | Google Scholar
  105. F. Roselli, P. Livrea, and O. F. X. Almeida, “CDK5 is essential for soluble amyloid β-induced degradation of GKAP and remodeling of the synaptic actin cytoskeleton,” PLoS ONE, vol. 6, no. 7, Article ID e23097, 2011, http://dx.plos.org/10.1371/journal.pone.0023097. View at: Publisher Site | Google Scholar
  106. A. Michelucci, T. Heurtaux, L. Grandbarbe, E. Morga, and P. Heuschling, “Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-β,” Journal of Neuroimmunology, vol. 210, no. 1-2, pp. 3–12, 2009, http://www.ncbi.nlm.nih.gov/pubmed/19269040. View at: Publisher Site | Google Scholar
  107. J. Y. Choi, J. Y. Kim, J. Y. Kim, J. Park, W. T. Lee, and J. E. Lee, “M2 Phenotype Microglia-derived Cytokine Stimulates Proliferation and Neuronal Differentiation of Endogenous Stem Cells in Ischemic Brain,” Experimental Neurobiology, vol. 26, no. 1, p. 33, 2017, http://www.ncbi.nlm.nih.gov/pubmed/28243165. View at: Publisher Site | Google Scholar
  108. M. A. Bouhlel, B. Derudas, E. Rigamonti et al., “PPARγ activation primes human monocytes into alternative m2 macrophages with anti-inflammatory properties,” Cell Metabolism, vol. 6, no. 2, pp. 137–143, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17681149. View at: Publisher Site | Google Scholar
  109. J. I. Odegaard, R. R. Ricardo-Gonzalez, M. H. Goforth et al., “Macrophage-specific PPARγ controls alternative activation and improves insulin resistance,” Nature, vol. 447, no. 7148, pp. 1116–1120, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17515919. View at: Publisher Site | Google Scholar
  110. G. J. Song, Y. Nam, M. Jo et al., “A novel small-molecule agonist of PPAR-γ potentiates an anti-inflammatory M2 glial phenotype,” Neuropharmacology, vol. 109, pp. 159–169, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27288982. View at: Publisher Site | Google Scholar
  111. A. Chawla, Y. Barak, L. Nagy, D. Liao, P. Tontonoz, and R. M. Evans, “PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation,” Nature Medicine, vol. 7, no. 1, pp. 48–52, 2001, http://www.ncbi.nlm.nih.gov/pubmed/11135615. View at: Publisher Site | Google Scholar
  112. M. Obulesu and M. J. Lakshmi, “Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues,” Neurochemical Research, vol. 39, no. 12, pp. 2301–2312, 2014, http://www.ncbi.nlm.nih.gov/pubmed/25322820. View at: Publisher Site | Google Scholar
  113. R. Castellani, K. Hirai, G. Aliev et al., “Role of mitochondrial dysfunction in Alzheimer's disease,” Journal of Neuroscience Research, vol. 70, no. 3, pp. 357–360, 2002, http://www.ncbi.nlm.nih.gov/pubmed/12391597. View at: Publisher Site | Google Scholar
  114. I. Bogacka, H. Xie, G. A. Bray, and S. R. Smith, “Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo,” Diabetes, vol. 54, no. 5, pp. 1392–1399, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15855325. View at: Publisher Site | Google Scholar
  115. L. Qiang, L. Wang, N. Kon et al., “Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ,” Cell, vol. 150, no. 3, pp. 620–632, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22863012. View at: Publisher Site | Google Scholar
  116. G. Haemmerle, T. Moustafa, G. Woelkart et al., “ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1,” Nature Medicine, vol. 17, no. 9, pp. 1076–1085, 2011, http://www.ncbi.nlm.nih.gov/pubmed/21857651. View at: Publisher Site | Google Scholar
  117. D. M. Muoio and T. R. Koves, “Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α: implications for metabolic disease,” Applied Physiology, Nutrition, and Metabolism, vol. 32, no. 5, pp. 874–883, 2007, http://www.ncbi.nlm.nih.gov/pubmed/18059612. View at: Publisher Site | Google Scholar
  118. W. Qin, V. Haroutunian, P. Katsel et al., “PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia,” JAMA Neurology, vol. 66, no. 3, pp. 352–361, 2009, http://www.ncbi.nlm.nih.gov/pubmed/19273754. View at: Publisher Site | Google Scholar
  119. P. Wareski, A. Vaarmann, V. Choubey et al., “PGC-1α and PGC-1β regulate mitochondrial density in neurons,” The Journal of Biological Chemistry, vol. 284, no. 32, pp. 21379–21385, 2009, http://www.ncbi.nlm.nih.gov/pubmed/19542216. View at: Publisher Site | Google Scholar
  120. J. M. Zolezzi, C. Silva-Alvarez, D. Ordenes et al., “Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?” PLoS ONE, vol. 8, no. 5, Article ID e64019, 2013, http://dx.plos.org/10.1371/journal.pone.0064019. View at: Publisher Site | Google Scholar
  121. L. Katsouri, Y. M. Lim, K. Blondrath et al., “PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 113, no. 43, pp. 12292–12297, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27791018. View at: Publisher Site | Google Scholar
  122. L. K. Russell, C. M. Mansfield, J. J. Lehman et al., “Cardiac-Specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-Dependent Manner,” Circulation Research, vol. 94, no. 4, pp. 525–533, 2004, http://www.ncbi.nlm.nih.gov/pubmed/14726475. View at: Publisher Site | Google Scholar
  123. S. Miura, E. Tomitsuka, Y. Kamei et al., “Overexpression of Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Leads to Muscle Atrophy with Depletion of ATP,” The American Journal of Pathology, vol. 169, no. 4, pp. 1129–1139, 2006, http://www.ncbi.nlm.nih.gov/pubmed/17003473. View at: Publisher Site | Google Scholar
  124. J. Clark, J. M. Silvaggi, T. Kiselak et al., “Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf,” PLoS ONE, vol. 7, no. 11, Article ID e48925, 2012, http://dx.plos.org/10.1371/journal.pone.0048925. View at: Publisher Site | Google Scholar
  125. C. Ciron, S. Lengacher, J. Dusonchet, P. Aebischer, and B. L. Schneider, “Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function,” Human Molecular Genetics, vol. 21, no. 8, pp. 1861–1876, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22246294. View at: Publisher Site | Google Scholar
  126. M.-C. Chiang, Y.-C. Cheng, H.-M. Chen, Y.-J. Liang, and C.-H. Yen, “Rosiglitazone promotes neurite outgrowth and mitochondrial function in N2A cells via PPARgamma pathway,” Mitochondrion, vol. 14, no. 1, pp. 7–17, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24370585. View at: Publisher Site | Google Scholar
  127. A. Prakash and A. Kumar, “Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of β-amyloid animal model of Alzheimer's disease,” Neurotoxicity Research, vol. 25, no. 4, pp. 335–347, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24277156. View at: Publisher Site | Google Scholar
  128. J. L. Marks, D. Porte, W. L. Stahl, and D. G. Baskin, “Localization of insulin receptor mRNA in rat brain by in situ hybridization,” Endocrinology, vol. 127, no. 6, pp. 3234–3236, 1990, http://www.ncbi.nlm.nih.gov/pubmed/2249648. View at: Publisher Site | Google Scholar
  129. J. W. Unger and M. Betz, “Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications,” Histology Histopathology Journal, vol. 13, no. 4, pp. 1215–1224, 1998, http://www.ncbi.nlm.nih.gov/pubmed/9810512. View at: Google Scholar
  130. G. A. Werther, A. Hogg, B. J. Oldfield et al., “Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry,” Endocrinology, vol. 121, no. 4, pp. 1562–1570, 1987, http://www.ncbi.nlm.nih.gov/pubmed/3653038. View at: Publisher Site | Google Scholar
  131. W. Zhao, H. Chen, H. Xu et al., “Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats,” The Journal of Biological Chemistry, vol. 274, no. 49, pp. 34893–34902, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10574963. View at: Publisher Site | Google Scholar
  132. J. Bloemer, S. Bhattacharya, R. Amin, and V. Suppiramaniam, “Impaired insulin signaling and mechanisms of memory loss,” Progress in Molecular Biology and Translational Science, vol. 121, pp. 413–449, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24373245. View at: Publisher Site | Google Scholar
  133. M. Schubert, D. Gautam, D. Surjo et al., “The role for neuronal insulin resistance in neurodegenerative diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 3100–3105, 2004, http://www.ncbi.nlm.nih.gov/pubmed/14981233. View at: Publisher Site | Google Scholar
  134. L. Ho, W. Qin, P. N. Pompl, Z. Xiang, J. Wang et al., “Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease,” The FASEB Journal, vol. 18, no. 7, pp. 902–904, 2004, http://www.ncbi.nlm.nih.gov/pubmed/15033922. View at: Publisher Site | Google Scholar
  135. A. R. Pathan, A. B. Gaikwad, B. Viswanad, and P. Ramarao, “Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats,” European Journal of Pharmacology, vol. 589, no. 1-3, pp. 176–179, 2008, http://www.ncbi.nlm.nih.gov/pubmed/18602098. View at: Publisher Site | Google Scholar
  136. X.-L. Li, S. Aou, Y. Oomura, N. Hori, K. Fukunaga, and T. Hori, “Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents,” Neuroscience, vol. 113, no. 3, pp. 607–615, 2002, http://www.ncbi.nlm.nih.gov/pubmed/12150780. View at: Publisher Site | Google Scholar
  137. E. Steen, B. M. Terry, E. J. Rivera et al., “Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–Is this type 3 diabetes?” Journal of Alzheimer's Disease, vol. 7, no. 1, pp. 63–80, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15750215. View at: Publisher Site | Google Scholar
  138. S. Hoyer and H. Lannert, “Inhibition of the Neuronal Insulin Receptor Causes Alzheimer-like Disturbances in Oxidative/Energy Brain Metabolism and in Behavior in Adult Rats,” Annals of the New York Academy of Sciences, vol. 893, no. 1, pp. 301–303, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10672254. View at: Publisher Site | Google Scholar
  139. G.-J. Chen, J. Xu, S. A. Lahousse, N. L. Caggiano, and S. M. De la Monte, “Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: Potential strategies for neuroprotection,” Journal of Alzheimer's Disease, vol. 5, no. 3, pp. 209–228, 2003, http://www.ncbi.nlm.nih.gov/pubmed/12897406. View at: Publisher Site | Google Scholar
  140. P. L. Mcclean, V. Parthsarathy, E. Faivre, and C. Holscher, “The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease,” The Journal of Neuroscience, vol. 31, no. 17, pp. 6587–6594, 2011, http://www.ncbi.nlm.nih.gov/pubmed/21525299. View at: Publisher Site | Google Scholar
  141. N. Pipatpiboon, W. Pratchayasakul, N. Chattipakorn, and S. C. Chattipakorn, “PPARγ agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets,” Endocrinology, vol. 153, no. 1, pp. 329–338, 2012, http://www.ncbi.nlm.nih.gov/pubmed/22109891. View at: Publisher Site | Google Scholar
  142. N. C. Inestrosa and L. Varela-Nallar, “Wnt signaling in the nervous system and in Alzheimer's disease,” Journal of Molecular Cell Biology, vol. 6, no. 1, pp. 64–74, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24549157. View at: Publisher Site | Google Scholar
  143. C. Tapia-Rojas and N. Inestrosa, “Loss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer's disease,” Neural Regeneration Research, vol. 13, no. 10, p. 1705, 2018, http://www.ncbi.nlm.nih.gov/pubmed/30136680. View at: Publisher Site | Google Scholar
  144. P. Cisternas, P. Salazar, C. Silva-Álvarez, L. F. Barros, and N. C. Inestrosa, “Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis,” The Journal of Biological Chemistry, vol. 291, no. 50, pp. 25950–25964, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27703002. View at: Publisher Site | Google Scholar
  145. E. A. Winkler, Y. Nishida, A. P. Sagare et al., “GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration,” Nature Neuroscience, vol. 18, no. 4, pp. 521–530, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25730668. View at: Publisher Site | Google Scholar
  146. Z. Chen and C. Zhong, “Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies,” Progress in Neurobiology, vol. 108, pp. 21–43, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23850509. View at: Google Scholar
  147. D. W. Cleveland, S. Y. Hwo, and M. W. Kirschner, “Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly,” Journal of Molecular Biology, vol. 116, no. 2, pp. 227–247, 1977, http://www.ncbi.nlm.nih.gov/pubmed/146092. View at: Publisher Site | Google Scholar
  148. A. Mietelska-Porowska, U. Wasik, M. Goras, A. Filipek, and G. Niewiadomska, “Tau protein modifications and interactions: their role in function and dysfunction,” International Journal of Molecular Sciences, vol. 15, no. 3, pp. 4671–4713, 2014, http://www.mdpi.com/1422-0067/15/3/4671. View at: Publisher Site | Google Scholar
  149. C. d'abramo, R. Ricciarelli, M. A. Pronzato, and P. Davies, “Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells,” Journal of Neurochemistry, vol. 98, no. 4, pp. 1068–1077, 2006, http://doi.wiley.com/10.1111/j.1471-4159.2006.03931.x. View at: Publisher Site | Google Scholar
  150. B. L. Adler, M. Yarchoan, H. M. Hwang et al., “Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition,” Neurobiology of Aging, vol. 35, no. 4, pp. 793–801, 2014, http://www.ncbi.nlm.nih.gov/pubmed/24239383. View at: Publisher Site | Google Scholar
  151. M. Dumont, C. Stack, C. Elipenahli et al., “Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice,” Human Molecular Genetics, vol. 21, no. 23, Article ID dds355, pp. 5091–5105, 2012. View at: Publisher Site | Google Scholar
  152. T. Falkenberg, A. K. Mohammed, B. Henriksson, H. Persson, B. Winblad, and N. Lindefors, “Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment,” Neuroscience Letters, vol. 138, no. 1, pp. 153–156, 1992, http://www.ncbi.nlm.nih.gov/pubmed/1407655. View at: Publisher Site | Google Scholar
  153. T. Kariharan, G. Nanayakkara, K. Parameshwaran et al., “Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression,” Neurobiology of Aging, vol. 36, no. 3, pp. 1451–1461, 2015, https://www.sciencedirect.com/science/article/pii/S0197458014006344?via%3Dihub. View at: Publisher Site | Google Scholar
  154. F. Plattner, M. Angelo, and K. P. Giese, “The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation,” The Journal of Biological Chemistry, vol. 281, no. 35, pp. 25457–25465, 2006, http://www.ncbi.nlm.nih.gov/pubmed/16803897. View at: Publisher Site | Google Scholar
  155. J. Chen, S. Li, W. Sun, J. Li, and J. Padmanabhan, “Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity,” PLoS ONE, vol. 10, no. 4, Article ID e0123864, 2015, http://dx.plos.org/10.1371/journal.pone.0123864. View at: Publisher Site | Google Scholar
  156. E. Thouennon, Y. Cheng, V. Falahatian, N. X. Cawley, and Y. P. Loh, “Rosiglitazone-activated PPARγ induces neurotrophic factor-α1 transcription contributing to neuroprotection,” Journal of Neurochemistry, vol. 134, no. 3, pp. 463–470, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25940785. View at: Publisher Site | Google Scholar
  157. K. M. Fuenzalida, M. C. Aguilera, D. G. Piderit et al., “Peroxisome Proliferator-activated Receptor Is a Novel Target of the Nerve Growth Factor Signaling Pathway in PC12 Cells,” The Journal of Biological Chemistry, vol. 280, no. 10, pp. 9604–9609, 2005, http://www.jbc.org/cgi/doi/10.1074/jbc.M409447200. View at: Publisher Site | Google Scholar
  158. L. Aloe, M. L. Rocco, P. Bianchi, and L. Manni, “Nerve growth factor: from the early discoveries to the potential clinical use,” Journal of Translational Medicine, vol. 10, no. 1, p. 239, 2012, http://www.ncbi.nlm.nih.gov/pubmed/23190582. View at: Publisher Site | Google Scholar
  159. J. M. Zolezzi, M. J. Santos, S. Bastías-Candia, C. Pinto, J. A. Godoy, and N. C. Inestrosa, “PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation,” Biological Reviews, vol. 92, no. 4, pp. 2046–2069, 2017, http://doi.wiley.com/10.1111/brv.12320. View at: Publisher Site | Google Scholar
  160. B. W. Miller, K. C. Willett, and A. R. Desilets, “Rosiglitazone and Pioglitazone for the Treatment of Alzheimer's Disease,” Annals of Pharmacotherapy, vol. 45, no. 11, pp. 1416–1424, 2011, http://journals.sagepub.com/doi/10.1345/aph.1Q238. View at: Publisher Site | Google Scholar
  161. M. T. Heneka, A. Fink, and G. Doblhammer, “Effect of pioglitazone medication on the incidence of dementia,” Annals of Neurology, vol. 78, no. 2, pp. 284–294, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25974006. View at: Publisher Site | Google Scholar
  162. D. S. Geldmacher, T. Fritsch, M. J. McClendon, and G. Landreth, “A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with alzheimer disease,” JAMA Neurology, vol. 68, no. 1, pp. 45–50, 2011, http://www.ncbi.nlm.nih.gov/pubmed/20837824. View at: Publisher Site | Google Scholar
  163. Takeda and Zinfandel Pharmaceuticals Discontinue TOMMORROW Trial Following Planned Futility Analysis, https://www.takeda.com/newsroom/newsreleases/2018/takeda-tommorrow-trial/.
  164. J. Liu, L. Wang, and J. Jia, “Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-Analysis,” Drugs & Aging, vol. 32, no. 1, pp. 57–65, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25504005. View at: Publisher Site | Google Scholar
  165. H. Cheng, Y. Shang, and L. Jiang, “The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis,” International Journal of Neuroscience, vol. 126, no. 4, pp. 299–307, 2015, http://www.ncbi.nlm.nih.gov/pubmed/26001206. View at: Publisher Site | Google Scholar
  166. B. W. Miller, K. C. Willett, and A. R. Desilets, “Rosiglitazone and Pioglitazone for the Treatment of Alzheimer's Disease,” Annals of Pharmacotherapy, vol. 45, no. 11, pp. 1416–1424, 2011, http://www.ncbi.nlm.nih.gov/pubmed/22028424. View at: Publisher Site | Google Scholar
  167. S. Gathiaka, G. Nanayakkara, T. Boncher et al., “Design, development and evaluation of novel dual PPARδ/PPARγ agonists,” Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 3, pp. 873–879, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23273519. View at: Publisher Site | Google Scholar
  168. K. Liu, L. Xu, J. P. Berger et al., “Discovery of a Novel Series of Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists for the Treatment of Type 2 Diabetes and Dyslipidemia,” Journal of Medicinal Chemistry, vol. 48, no. 7, pp. 2262–2265, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15801817. View at: Publisher Site | Google Scholar
  169. L. S. Higgins and A. M. Depaoli, “Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation,” American Journal of Clinical Nutrition, vol. 91, no. 1, pp. 267S–272S, 2010, https://academic.oup.com/ajcn/article/91/1/267S/4597134. View at: Publisher Site | Google Scholar
  170. M. Laplante, H. Sell, K. L. MacNaul, D. Richard, J. P. Berger, and Y. Deshaies, “PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion,” Diabetes, vol. 52, no. 2, pp. 291–299, 2003, http://www.ncbi.nlm.nih.gov/pubmed/12540599. View at: Publisher Site | Google Scholar
  171. J. L. Oberfield, J. L. Collins, C. P. Holmes et al., “A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 96, no. 11, pp. 6102–6106, 1999, http://www.ncbi.nlm.nih.gov/pubmed/10339548. View at: Publisher Site | Google Scholar
  172. E. Burgermeister, A. Schnoebelen, A. Flament et al., “A novel partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1α, prevents triglyceride accumulation, and potentiates insulin signaling in vitro,” Molecular Endocrinology, vol. 20, no. 4, pp. 809–830, 2006, http://www.ncbi.nlm.nih.gov/pubmed/16373399. View at: Publisher Site | Google Scholar
  173. J. P. Berger, A. E. Petro, K. L. Macnaul et al., “Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator,” Molecular Endocrinology, vol. 17, no. 4, pp. 662–676, 2003, http://www.ncbi.nlm.nih.gov/pubmed/12554792. View at: Publisher Site | Google Scholar
  174. S.-H. Sheu, T. Kaya, D. J. Waxman, and S. Vajda, “Exploring the binding site structure of the PPARγ ligand-binding domain by computational solvent mapping,” Biochemistry, vol. 44, no. 4, pp. 1193–1209, 2005, http://www.ncbi.nlm.nih.gov/pubmed/15667213. View at: Publisher Site | Google Scholar
  175. L. L. Atkinson, M. A. Fischer, and G. D. Lopaschuk, “Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis,” The Journal of Biological Chemistry, vol. 277, no. 33, pp. 29424–29430, 2002, http://www.ncbi.nlm.nih.gov/pubmed/12058043. View at: Publisher Site | Google Scholar
  176. J. B. Bruning, M. J. Chalmers, S. Prasad et al., “Partial agonists activate PPARγ using a helix 12 independent mechanism,” Structure, vol. 15, no. 10, pp. 1258–1271, 2007, http://www.ncbi.nlm.nih.gov/pubmed/17937915. View at: Publisher Site | Google Scholar
  177. I. A. Voutsadakis, “Peroxisome proliferator activated receptor-γ and the ubiquitin-proteasome system in colorectal cancer,” World Journal of Gastrointestinal Oncology, vol. 2, no. 5, pp. 235–241, 2010, http://www.ncbi.nlm.nih.gov/pubmed/21160623. View at: Publisher Site | Google Scholar
  178. N. Viswakarma, Y. Jia, L. Bai et al., “Coactivators in PPAR-Regulated Gene Expression,” PPAR Research, Article ID 250126, pp. 1–21, 2010, http://www.ncbi.nlm.nih.gov/pubmed/20814439. View at: Publisher Site | Google Scholar
  179. S. M. Watkins, P. R. Reifsnyder, H. Pan, J. B. German, and E. H. Leiter, “Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone,” Journal of Lipid Research, vol. 43, no. 11, pp. 1809–1817, 2002, http://www.ncbi.nlm.nih.gov/pubmed/12401879. View at: Publisher Site | Google Scholar
  180. M. Einstein, T. E. Akiyama, G. A. Castriota et al., “The differential interactions of peroxisome proliferator-activated receptor γ ligands with Tyr473 is a physical basis for their unique biological activities,” Molecular Pharmacology, vol. 73, no. 1, pp. 62–74, 2008, http://www.ncbi.nlm.nih.gov/pubmed/17940191. View at: Publisher Site | Google Scholar
  181. L. Cui, H. Jeong, F. Borovecki, C. N. Parkhurst, N. Tanese, and D. Krainc, “Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration,” Cell, vol. 127, no. 1, pp. 59–69, 2006, http://www.ncbi.nlm.nih.gov/pubmed/17018277. View at: Publisher Site | Google Scholar
  182. M. H. Karimfar, K. Haghani, A. Babakhani, and S. Bakhtiyari, “Rosiglitazone, but Not Epigallocatechin-3-Gallate, Attenuates the Decrease in PGC-1α Protein Levels in Palmitate-Induced Insulin-Resistant C2C12 Cells,” Lipids, vol. 50, no. 6, pp. 521–528, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25893813. View at: Publisher Site | Google Scholar
  183. X. Kong, R. Wang, Y. Xue et al., “Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis,” PLoS ONE, vol. 5, no. 7, Article ID e11707, 2010, http://dx.plos.org/10.1371/journal.pone.0011707. View at: Publisher Site | Google Scholar
  184. X. Zhang, X. Ren, Q. Zhang et al., “PGC-1α/ERRα-Sirt3 pathway regulates DAergic neuronal death by directly deacetylating SOD2 and ATP synthase β,” Antioxidants & Redox Signaling, vol. 24, no. 6, pp. 312–328, 2016, http://www.ncbi.nlm.nih.gov/pubmed/26421366. View at: Publisher Site | Google Scholar
  185. H. Jiang, S. Kang, S. Zhang et al., “Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons,” eNeuro, vol. 3, no. 4, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27622213. View at: Publisher Site | Google Scholar
  186. J. Lin, P.-H. Wu, P. T. Tarr et al., “Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice,” Cell, vol. 119, no. 1, pp. 121–135, 2004, http://www.ncbi.nlm.nih.gov/pubmed/15454086. View at: Publisher Site | Google Scholar
  187. G. Sweeney and J. Song, “The association between PGC-1α and Alzheimer's disease,” Anatomy & Cell Biology, vol. 49, no. 1, pp. 1–6, 2016, http://www.ncbi.nlm.nih.gov/pubmed/27051562. View at: Publisher Site | Google Scholar

Copyright © 2018 Manoj Govindarajulu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles