Central role of PPARγ in Alzheimer’s disease: From pathophysiology to potential therapies

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the deposition of amyloid-beta (Aβ), neurofibrillary tangles, and chronic neuroinflammation, resulting in progressive cognitive decline and neuronal damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a key role in the regulation of inflammation, glucose homeostasis, lipid metabolism, and mitochondrial function, thus providing a promising therapeutic target for AD management. PPARγ plays a significant role in key pathological processes in AD, including Aβ generation and impaired clearance, tau protein hyperphosphorylation, neuroinflammatory responses, and mitochondrial dysfunction. PPARγ agonists, such as pioglitazone and rosiglitazone, have demonstrated potential benefits in preclinical and clinical studies, such as reducing neuroinflammation, improving mitochondrial biogenesis, modulating insulin signaling, and potentially improving cognitive function. Nevertheless, challenges remain, such as adverse effects, for example, weight gain and limited blood-brain barrier (BBB) permeability of existing agonists. This review discusses the therapeutic potential of PPARγ-mediated strategies for AD, focusing on the development of BBB-penetrable agonists and multimodal therapies aimed at simultaneously addressing multiple pathological aspects. It also highlights the need for comprehensive research to understand the mechanisms by which PPARγ modulates AD pathology. This review on the multifaceted role of PPARγ in AD progression will inspire novel therapeutic approaches with combinatorial strategies and precise modulation of PPARγ activity. Thus, targeting PPARγ may provide some effective treatments for the improvement of disease trajectory in patients with AD.