Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo Onoda, Japan (T.H.); Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Japan (K.Y., M.I., A.T., K.O.); Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan (Y.N.); and Section of Neuromedical Science, Division of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan (C.T.)
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo Onoda, Japan (T.H.); Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Japan (K.Y., M.I., A.T., K.O.); Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan (Y.N.); and Section of Neuromedical Science, Division of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan (C.T.).
Mol Pharmacol. 2023 May;103(5):266-273. doi: 10.1124/molpharm.121.000468. Epub 2023 Mar 3.
Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid 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 aggregation. Importantly, we also found that alkannin inhibited amyloid aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit -sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid -induced neuronal cell death in PC12 cells, ameliorated amyloid aggregation in the AD model of (), and inhibited chemotaxis observed in AD , suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid 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 Overall, alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in Alzheimer's disease.
阿尔茨海默病（AD）是一种神经退行性疾病，伴有记忆下降和认知功能障碍。淀粉样蛋白聚集形成和积累可能是 AD 病理生理学的潜在机制之一。因此，能够抑制淀粉样蛋白聚集的化合物可能对治疗有用。基于这一假设，我们筛选了用于汉方药的植物化合物的化学伴侣活性，并鉴定出alkanin 具有这种特性。进一步的分析表明，alkanin 可以抑制淀粉样蛋白的聚集。重要的是，我们还发现 alkannin 可以抑制聚集物形成后淀粉样蛋白的聚集。通过圆二色性光谱分析，发现 alkannin 可以抑制 β-折叠结构的形成，这是一种易于聚集的有毒结构。此外，alkanin 可以减轻 PC12 细胞中的淀粉样蛋白诱导的神经元细胞死亡，改善 中的 AD 模型中的淀粉样蛋白聚集，并抑制 AD 中观察到的趋化作用，这表明 alkannin 可能在体内抑制神经退行性变。总的来说，这些结果表明 alkannin 可能具有抑制 AD 中淀粉样蛋白聚集和神经元细胞死亡的新的药理学特性。
淀粉样蛋白β聚集形成和积累是阿尔茨海默病病理生理学的潜在机制之一。我们发现 alkannin 具有化学伴侣活性，可抑制淀粉样蛋白β的β-折叠结构形成及其聚集、神经元细胞死亡和阿尔茨海默病表型。总的来说，alkannin 可能具有抑制阿尔茨海默病中淀粉样蛋白β聚集和神经元细胞死亡的新的药理学特性。
