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

Autor:	Kim HJ; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea., Kim H; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Song J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Hong JY; Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea.; Department of Systems Biology, Yonsei University, Seoul 03722, Republic of Korea., Lee EH; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Londhe AM; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Choi JW; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea., Park SJ; Cureverse, lnc., H2 building, KIST, Seoul 02792, Republic of Korea., Oh E; Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea., Yoon H; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Hwang H; Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea., Hahn D; Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea.; School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea., Jung K; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Kwon S; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Kadayat TM; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Ma MJ; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Joo J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Kim J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Bae JH; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Hwang H; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Pae AN; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Cho SJ; Cureverse, lnc., H2 building, KIST, Seoul 02792, Republic of Korea., Park JH; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Chin J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.; Cureverse, lnc., H2 building, KIST, Seoul 02792, Republic of Korea., Kang H; Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea.; Research Institute of Oceanography, Seoul National University, NS-80, Seoul 08826, Republic of Korea., Park KD; Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2024 Sep 16; Vol. 14 (16), pp. 6088-6108. Date of Electronic Publication: 2024 Sep 16 (Print Publication: 2024).
DOI:	10.7150/thno.96707
Abstrakt:	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. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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