Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer's Disease: An Update

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder, characterized by the deposition of amyloid-β within the brain parenchyma resulting into a significant decline in cognitive functions during the late stage of the disease. The disease patho- physiological conditions is recognized by the perturbation of synaptic function, energy and lipid metabolism. Deposition of amyloid plaques triggers inflammation upon the induction of microglia. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to play important role in the regulation of glucose absorption, homeostasis of lipid metabolism and further involves in repressing the expression of genes related to inflammation. Thus, agonists of this receptor represent an attractive therapeutic target for AD. In recent, both clinical and preclinical studies show that use of Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD related pathology. Thus, PPARγ signify a significant new therapeutic target in treating AD. In this review, we have shed some light on the recent progress of how, PPARγ agonist selectively modulated different cellular targets in AD and its amazing potential in the treatment of AD.

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

“…Pioglitazone, an agonist of PPARγ, has been shown to halt progression of Parkinsonism in a rodent model, ostensibly by inhibiting microglial inflammation and proliferation (Machado et al, 2019), although it is difficult to conclude if this is a direct effect on microglia given that the compound can affect a number of cells in these models. Targeting PPARγ for therapeutic benefit in AD has also recently been proposed (Khan et al, 2019). Interestingly we found that whilst the deficits in maximal respiration, glycolysis and glycolytic capacity observed in the R47H variants can be rescued by the PPARγ agonist, these deficits in the NHD hypomorphs cannot, suggesting that the reduced levels of PPARγ protein observed in these variants and the limited levels of mature TREM2 may have an uncoupling effect on the signalling to and from PPARγ.…”

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

“…Pioglitazone, an agonist of PPARγ, has been shown to halt progression of Parkinsonism in a rodent model, ostensibly by inhibiting microglial inflammation and proliferation, although it is difficult to conclude if this is a direct effect on microglia given that the compound can affect a number of cells in these models. Targeting PPARγ for therapeutic benefit in AD has also recently been proposed . Interestingly we found that whilst the deficits in maximal respiration, glycolysis and glycolytic capacity observed in the R47H variants can be rescued by the PPARγ agonist, these deficits in the NHD hypomorphs cannot, suggesting that the reduced levels of PPARγ protein observed in these variants and the limited levels of mature TREM2 may have an uncoupling effect on the signaling to and from PPARγ.…”

“…Targeting PPARγ for therapeutic benefit in AD has also recently been proposed. 50 Interestingly we found that whilst the deficits in maximal respiration, glycolysis and glycolytic capacity observed in the R47H variants can be rescued by the PPARγ agonist, these deficits in the NHD hypomorphs cannot, suggesting that the reduced levels of PPARγ protein observed in these variants and the limited levels of mature TREM2 may have an uncoupling effect on the signaling to and from PPARγ. Furthermore, preincubating R47H het iPS-Mg with pioglitazone prior to LPS/IFNγ exposure rescued the energetic metabolic phenotype, strongly linking PPARγ function to the locked immunometabolic switch observed in TREM2 hypomorphic lines.…”

Systems Pharmacology Approach to Investigate the Mechanism of Kai-Xin-San in Alzheimer’s Disease

“…For example, inhibitors of ACHE (e.g., donepezil) can provide modest symptomatic relief for AD patients (Arvanitakis et al, 2019). Recently, both preclinical and clinical studies have indicated that PPARG agonists can improve learning and memory abilities in AD patients (Khan et al, 2019). BACE1 inhibitors have also been reported to repress the generation of neurotoxic amyloid protein (Dobrowolska Zakaria and Vassar, 2018; Moussa-Pacha et al, 2019).…”