Reversal of Memory Deficits in Alzheimer’s Disease Mouse Models by a Highly Potent and Selective PPAR-Delta Agonist 2387

Description Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by neurotoxicity, excessive inflammation, and cognitive deficits. Peroxisome proliferator-activated receptor delta (PPARδ) is considered a potential therapeutic target for AD, although its regulatory mechanisms and therapeutic potential are not fully understood. In this study, we synthesized a novel PPARδ agonist, 5a, containing a selenazole ring and confirmed its binding to PPARδ through X-ray crystallography. We evaluated the drug-like properties of 5a, including its impact on cytochrome P450, microsomal stability, pharmacokinetics, and mutagenicity. Additionally, we investigated the anti-inflammatory effects of 5a in lipopolysaccharide-stimulated BV-2 microglial cells and a neuroinflammatory mouse model. The therapeutic efficacy of 5a was assessed in AD mouse models with scopolamine-induced memory impairment and APP/PS1 transgenic mice, examining cognitive function, glial reactivity, and amyloid pathology. The findings suggest that specific activation of PPARδ by 5a significantly reduces amyloid plaque deposition, glial hyperactivation, and inflammatory responses, improving learning and memory in AD models, thereby highlighting the potential of PPARδ as a promising drug target for AD treatment. Topic Categories Neuroimmunology (NEUR)