期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：3
DOI：10.1073/pnas.2115082119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
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.
关键词：enAlzheimer’s diseaseASM direct inhibitorGHSR1 alpha agonistmemory improvementsmall compound
