Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

Author:

Park Min Hee12,Park Kang Ho12,Choi Byung Jo13,Han Wan Hui12,Yoon Hee Ji12,Jung Hye Yoon12,Lee Jihoon4,Song Im-Sook4,Lim Dong Yu5,Choi Min-Koo5ORCID,Lee Yang-Ha6,Park Cheol-Min6,Wang Ming7,Jo Jihoon89,Kim Hee-Jin10ORCID,Kim Seung Hyun10ORCID,Schuchman Edward H.11,Jin Hee Kyung13,Bae Jae-sung12

Affiliation:

1. KNU Alzheimer’s Disease Research Institute, Kyungpook National University, Daegu 41566, South Korea

2. Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, South Korea

3. Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea

4. BK21 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

5. College of Pharmacy, Dankook University, Cheon-an 31116, South Korea

6. Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea

7. BioMedical Sciences Graduate Program, Chonnam National University, Hwasun 58128, South Korea

8. Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea

9. Department of Neurology, Chonnam National University Medical School, Gwangju 501-757, South Korea

10. Department of Neurology, Hanyang University College of Medicine, Seoul 04763, South Korea

11. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029

Abstract

Significance Since Alzheimer’s disease (AD) is a multifaceted neurodegenerative disease, multitargeted therapeutic approaches are likely required for effective AD treatment. The importance of acid sphingomyelinase (ASM) activation in the various neuropathological features of AD is well-known. Therefore, in this study, we focused on identifying an efficient, direct inhibitor of ASM activity. We found that KARI 201 was a highly selective ASM activity inhibitor without any off-target effects. Through RNA-sequencing analysis in brains of AD mice, we also unexpectedly uncovered the role of KARI 201 as a ghrelin receptor agonist. This dual role of KARI 201 in neurons led to improvement of Aβ accumulation, neuroinflammation, synapse loss, hippocampal neurogenesis, and memory dysfunction in AD mice.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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