Highly potent and selective PPAR6 agonist reverses memory deficits in mouse models of Alzheimer's disease

초록

Rationale: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) 6 is a potential target for AD. However, its regulatory mechanisms and therapeutic potential in AD remain unclear. We aimed to investigate if the activation of PPAR6 using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. Methods: We synthesized a novel PPAR6 agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPAR6. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a , the most potent and selective PPAR6 agonist, was confirmed to bind hPPAR6 in a complex by X-ray crystallographic analysis. PPAR6 activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a inhibited amyloid plaque deposition by suppressing the expression of neuronal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and reduced abnormal glial hyperactivation and inflammatory responses, resulting in improved learning and memory in the APP/PS1 mouse model of AD. Conclusion: We identified that specific activation of PPAR6 provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPAR6 as a promising drug target for treating AD.

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