{"title":"Alkannin Attenuates Amyloid <i>β</i> Aggregation and Alzheimer's Disease Pathology.","authors":"Toru Hosoi, Kyosuke Yazawa, Michihiro Imada, Akari Tawara, Chihiro Tohda, Yasuyuki Nomura, Koichiro Ozawa","doi":"10.1124/molpharm.121.000468","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid <i>β</i> formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid <i>β</i> aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid <i>β</i> aggregation. Importantly, we also found that alkannin inhibited amyloid <i>β</i> aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit <i>β</i>-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid <i>β</i>-induced neuronal cell death in PC12 cells, ameliorated amyloid <i>β</i> aggregation in the AD model of <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), and inhibited chemotaxis observed in AD <i>C. elegans</i>, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid <i>β</i> aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid β formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit β-sheet structure formation of amyloid β and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in <i>C. elegans.</i> Overall, alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in Alzheimer's disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/molpharm.121.000468","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 1
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid β formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid β aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid β aggregation. Importantly, we also found that alkannin inhibited amyloid β aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit β-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid β-induced neuronal cell death in PC12 cells, ameliorated amyloid β aggregation in the AD model of Caenorhabditis elegans (C. elegans), and inhibited chemotaxis observed in AD C. elegans, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid β formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit β-sheet structure formation of amyloid β and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in C. elegans. Overall, alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in Alzheimer's disease.
期刊介绍:
Molecular Pharmacology publishes findings derived from the application of innovative structural biology, biochemistry, biophysics, physiology, genetics, and molecular biology to basic pharmacological problems that provide mechanistic insights that are broadly important for the fields of pharmacology and toxicology. Relevant topics include:
Molecular Signaling / Mechanism of Drug Action
Chemical Biology / Drug Discovery
Structure of Drug-Receptor Complex
Systems Analysis of Drug Action
Drug Transport / Metabolism