Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk 2024-11-07T02:30:27Z 2024-11-07T02:30:27Z 2024-11-06 2024-09 1838-7640 https://pubs.kist.re.kr/handle/201004/151005 Rationale: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) δ 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 PPARδ using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. 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 PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ 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 PPARδ provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPARδ as a promising drug target for treating AD. English Ivyspring International Publisher Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease Article 10.7150/thno.96707 1 Theranostics, v.14, no.16, pp.6088 - 6108 Theranostics 14 16 6088 6108 Y scie scopus 001361061300001 Medicine, Research & Experimental Research & Experimental Medicine Article KAPPA-B ACTIVITY TRANSCRIPTION FACTORS CYTOKINE PRODUCTION BETA/DELTA AGONIST NUCLEAR RECEPTORS INFLAMMATION DELTA BRAIN DYSFUNCTION PROLIFERATOR-ACTIVATED RECEPTOR PPAR delta agonist Alzheimer&apos s disease anti-inflammation glial activation BACE1