한빛사논문
- 조회1,018
Min Hee Parka,b,1, Kang Ho Parka,b,1, Byung Jo Choia,c, Wan Hui Hana,b, Hee Ji Yoona,b, Hye Yoon Junga,b, Jihoon Leed, Im-Sook Songd, Dong Yu Lime, Min-Koo Choie, Yang-Ha Leef, Cheol-Min Parkf, Ming Wangg, Jihoon Joh,i, Hee-Jin Kimj, Seung Hyun Kimj, Edward H. Schuchmank, Hee Kyung Jina,c,2, and Jae-sung Baea,b,2
aKNU Alzheimer’s Disease Research Institute, Kyungpook National University, Daegu 41566, South Korea; bDepartment of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, South Korea; cDepartment of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea; dBK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, South Korea; eCollege of Pharmacy, Dankook University, Cheon-an 31116, South Korea; fDepartment of Chemistry, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea; gBioMedical Sciences Graduate Program, Chonnam National University, Hwasun 58128, South Korea; hDepartment of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea; iDepartment of Neurology, Chonnam National University Medical School, Gwangju 501-757, South Korea; jDepartment of Neurology, Hanyang University College of Medicine, Seoul 04763, South Korea; and kDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
1M.H.P. and K.H.P. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.
Alzheimer’s disease, ASM direct inhibitor, GHSR1 alpha agonist, memory improvement, small compound
논문정보
- Research article
- 2022년 01월 (BRIC 등록일 2022-01-20)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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