陶氏病
阿米必利
神经科学
τ蛋白
药物发现
失智症
药理学
高磷酸化
化学
神经退行性变
痴呆
心理学
生物
医学
疾病
阿尔茨海默病
生物信息学
细胞生物学
内科学
抗精神病药
精神分裂症(面向对象编程)
精神科
激酶
作者
Kathrin Jahreis,Alina Brüge,Saskia Borsdorf,Franziska E. Müller,Wei-Lun Sun,Shaobo Jia,Dong Min Kang,Nicolette Boesen,Sera Shin,Sungsu Lim,Anastasia Koroleva,Grzegorz Satała,Andrzej J. Bojarski,Elena Rakuša,Anne Fink,Gabriele Doblhammer‐Reiter,Yun Kyung Kim,Alexander Dityatev,Evgeni Ponimaskin,Josephine Labus
摘要
Abstract INTRODUCTION Hyperphosphorylation and aggregation of the microtubule‐associated protein tau cause the development of tauopathies, such as Alzheimer's disease and frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5‐HT7R) activity and pathological tau aggregation. Here, we evaluated 5‐HT7R inverse agonists as novel drugs in the treatment of tauopathies. METHODS Based on structural homology, we screened multiple approved drugs for their inverse agonism toward 5‐HT7R. Therapeutic potential was validated using biochemical, pharmacological, microscopic, and behavioral approaches in different cellular models including tau aggregation cell line HEK293 tau bimolecular fluorescence complementation, primary mouse neurons, and human induced pluripotent stem cell–derived neurons carrying an FTD‐associated tau mutation as well as in two mouse models of tauopathy. RESULTS Antipsychotic drug amisulpride is a potent 5‐HT7R inverse agonist. Amisulpride ameliorated tau hyperphosphorylation and aggregation in vitro. It further reduced tau pathology and abrogated memory impairment in mice. DISCUSSION Amisulpride may be a disease‐modifying drug for tauopathies.
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