Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer's disease (AD), but whether and how tau dysregulates AHN in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.

中文翻译：

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磷酸化tau的中间神经元积累通过抑制GABA能传递而损害成年海马神经发生。

磷酸化tau积累和成人海马神经发生（AHN）损伤均对阿尔茨海默氏病（AD）的认知下降做出重要贡献，但tau是否以及如何在AD中失调AHN仍知之甚少。在这里，我们发现AD患者和小鼠的齿状回（DG）的GABA能中间神经元中磷酸化tau的大量积累。小鼠DG中神经元中人tau（hTau）的特异性过表达诱导AHN缺陷，但增加了神经干细胞来源的星形胶质细胞增生，与GABA的下调和邻近的兴奋性神经元的过度活化有关。兴奋性神经元的化学生成抑制或药理上增强的GABA能节律挽救了tau诱导的AHN缺陷并改善了情境认知。