한빛사논문
Hyeon Jeong Kim1, Haelee Kim2, Jaeyoung Song2, Jun Young Hong3,4, Elijah Hwejin Lee1,5, Ashwini M. Londhe1,5, Ji Won Choi1, Sun Jun Park6, Eunseok Oh3, Heeseok Yoon2, Hoosang Hwang3, Dongyup Hahn3,7, Kyungjin Jung2, Sugyeong Kwon2, Tara Man Kadayat2, Min Jung Ma2, Jeongmin Joo2, Jina Kim2, Jae Hyun Bae2, Hayoung Hwang2, Ae Nim Pae1,5, Sung Jin Cho6, Jong-Hyun Park1,5,*, Jungwook Chin2,6,*, Heonjoong Kang3,8,*, Ki Duk Park1,5,*
1Center for Brain Disorders, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
2New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
3Laboratory of Marine Drugs, School of Earth and Environmental Sciences, Seoul National University, NS-80 Seoul 08826, Republic of Korea.
4Department of Systems Biology, Yonsei University, Seoul 03722, Republic of Korea.
5Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
6Cureverse, lnc., H2 building, KIST, Seoul 02792, Republic of Korea.
7School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea.
8Research Institute of Oceanography, Seoul National University, NS-80, Seoul 08826, Republic of Korea.
*Corresponding authors: Ki Duk Park, Ph.D., Heonjoong Kang, Ph.D., Jong-Hyun Park, Ph.D.
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.
논문정보
관련 링크
연구자 키워드
연구자 ID
소속기관 논문보기
관련분야 논문보기