Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
Alzheimers Dement. 2023 Dec;19(12):5482-5497. doi: 10.1002/alz.13090. Epub 2023 May 23.
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.
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.
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.
Amisulpride may be a disease-modifying drug for tauopathies.
微管相关蛋白 tau 的过度磷酸化和聚集导致 tau 病的发生，如阿尔茨海默病和额颞叶痴呆（FTD）。我们最近发现组成型血清素受体 7（5-HT7R）活性与病理性 tau 聚集之间存在因果关系。在这里，我们评估了 5-HT7R 反向激动剂作为治疗 tau 病的新型药物。
基于结构同源性，我们筛选了多种已批准的药物，以评估它们对 5-HT7R 的反向激动作用。在包括 tau 聚集细胞系 HEK293 tau 双分子荧光互补、原代小鼠神经元和携带 FTD 相关 tau 突变的人诱导多能干细胞衍生神经元在内的不同细胞模型中，以及在两种 tau 病小鼠模型中，通过生化、药理学、显微镜和行为方法验证了治疗潜力。
抗精神病药物氨磺必利是一种有效的 5-HT7R 反向激动剂。氨磺必利可改善体外 tau 过度磷酸化和聚集。它进一步减少 tau 病理学并改善了小鼠的记忆障碍。
氨磺必利可能是一种治疗 tau 病的疾病修饰药物。
