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dc.contributor.authorKim, Hyeon Jeong-
dc.contributor.authorKim, Haelee-
dc.contributor.authorSong, Jaeyoung-
dc.contributor.authorHong, Jun Young-
dc.contributor.authorLee, Elijah Hwejin-
dc.contributor.authorLondhe, Ashwini M-
dc.contributor.authorChoi, Ji Won-
dc.contributor.authorPark, Sun Jun-
dc.contributor.authorOh, Eunseok-
dc.contributor.authorYoon, Heeseok-
dc.contributor.authorHwang, Hoosang-
dc.contributor.authorHahn, Dongyup-
dc.contributor.authorJung, Kyungjin-
dc.contributor.authorKwon, Sugyeong-
dc.contributor.authorKadayat, Tara Man-
dc.contributor.authorMa, Min Jung-
dc.contributor.authorJoo, Jeongmin-
dc.contributor.authorKim, Jina-
dc.contributor.authorBae, Jae Hyun-
dc.contributor.authorHwang, Hayoung-
dc.contributor.authorPae, Ae Nim-
dc.contributor.authorCho, Sung Jin-
dc.contributor.authorPark, Jong Hyun-
dc.contributor.authorChin, Jungwook-
dc.contributor.authorKang, Heonjoong-
dc.contributor.authorPark, Ki Duk-
dc.date.accessioned2024-11-07T02:30:27Z-
dc.date.available2024-11-07T02:30:27Z-
dc.date.created2024-11-06-
dc.date.issued2024-09-
dc.identifier.issn1838-7640-
dc.identifier.urihttps://pubs.kist.re.kr/handle/201004/151005-
dc.description.abstractRationale: 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.-
dc.languageEnglish-
dc.publisherIvyspring International Publisher-
dc.titleHighly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease-
dc.typeArticle-
dc.identifier.doi10.7150/thno.96707-
dc.description.journalClass1-
dc.identifier.bibliographicCitationTheranostics, v.14, no.16, pp.6088 - 6108-
dc.citation.titleTheranostics-
dc.citation.volume14-
dc.citation.number16-
dc.citation.startPage6088-
dc.citation.endPage6108-
dc.description.isOpenAccessY-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
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