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Abstract：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. 
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