Tauopathies comprise a heterogeneous family of neurodegenerative diseases characterized by pathological accumulation of hyperphosphorylated Tau protein. Pathological changes in serotonergic signaling have been associated with tauopathy etiology, but the underlying mechanisms remain poorly understood. Here, we studied the role of the serotonin receptor 7 (5-HT7R), in a mouse model of tauopathy induced by overexpressing the human Tau[R406W] mutant associated with inherited forms of frontotemporal dementia. We showed that the constitutive 5-HT7R activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures (HBTS) through G-protein-independent, CDK5-dependent mechanism. We also showed that 5-HT7R physically interacts with CDK5. At the systemic level, 5-HT7R-mediated CDK5 activation induces HBTS leading to neuronal death, reduced long-term potentiation (LTP), and impaired memory in mice. Specific blockade of constitutive 5-HT7R activity in neurons that overexpressed Tau[R406W] prevents Tau hyperphosphorylation, aggregation, and neurotoxicity. Moreover, 5-HT7R knockdown in the prefrontal cortex fully abrogates Tau[R406W]-induced LTP deficits and memory impairments. Thus, 5-HT7R/CDK5 signaling emerged as a new, promising target for tauopathy treatments.

Tauopathies 包括一个异质的神经退行性疾病家族，其特征是过度磷酸化 Tau 蛋白的病理性积累。血清素信号的病理变化与 tau 蛋白病病因有关，但其潜在机制仍知之甚少。在这里，我们研究了血清素受体 7 (5-HT7R) 在与遗传性额颞叶痴呆相关的人类 Tau[R406W] 突变体过表达诱导的 tau 蛋白病变小鼠模型中的作用。我们表明，Tau 过度磷酸化和通过 G 蛋白非依赖性、CDK5 依赖性机制形成高度捆绑的 Tau 结构 (HBTS) 需要组成性 5-HT7R 活性。我们还展示了 5-HT7R 与 CDK5 的物理相互作用。在系统层面，5-HT7R 介导的 CDK5 激活诱导 HBTS，导致神经元死亡、长期增强 (LTP) 降低和小鼠记忆力受损。在过表达 Tau[R406W] 的神经元中对组成型 5-HT7R 活性的特异性阻断可防止 Tau 过度磷酸化、聚集和神经毒性。此外，前额叶皮层中的 5-HT7R 敲低完全消除了 Tau[R406W] 诱导的 LTP 缺陷和记忆障碍。因此，5-HT7R/CDK5 信号转导成为 tau 蛋白病治疗的一个新的、有希望的靶点。前额叶皮层中的 5-HT7R 敲低完全消除了 Tau[R406W] 诱导的 LTP 缺陷和记忆障碍。因此，5-HT7R/CDK5 信号转导成为 tau 蛋白病治疗的一个新的、有希望的靶点。前额叶皮层中的 5-HT7R 敲低完全消除了 Tau[R406W] 诱导的 LTP 缺陷和记忆障碍。因此，5-HT7R/CDK5 信号转导成为 tau 蛋白病治疗的一个新的、有希望的靶点。