TY - JOUR
T1 - Alkannin Attenuates Amyloid β Aggregation and Alzheimer's Disease Pathology
AU - Hosoi, Toru
AU - Yazawa, Kyosuke
AU - Imada, Michihiro
AU - Tawara, Akari
AU - Tohda, Chihiro
AU - Nomura, Yasuyuki
AU - Ozawa, Koichiro
N1 - Publisher Copyright:
© 2023 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - 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 b 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 b-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.
AB - 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 b 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 b-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.
UR - http://www.scopus.com/inward/record.url?scp=85152601881&partnerID=8YFLogxK
U2 - 10.1124/molpharm.121.000468
DO - 10.1124/molpharm.121.000468
M3 - 学術論文
C2 - 36868792
AN - SCOPUS:85152601881
SN - 0026-895X
VL - 103
SP - 266
EP - 273
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -