Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease
- Authors
- 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
- Issue Date
- 2024-09
- Publisher
- Ivyspring International Publisher
- Citation
- Theranostics, v.14, no.16, pp.6088 - 6108
- Abstract
- 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.
- ISSN
- 1838-7640
- URI
- https://pubs.kist.re.kr/handle/201004/151005
- DOI
- 10.7150/thno.96707
- Appears in Collections:
- KIST Article > 2024
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