Liu Fei, Cui Jiu-Jing, Li Xiao-Lin, Zhang Zeng-Min, Liang Shao-Hua, Sun Yi, Li Jing-Min, Qu Hong-Lin, Ye Jing, Guo Qi-Peng, Zheng Quan, Liu Yong-Feng
Department of Human Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai, China.
School of Rehabilitation Medicine, Binzhou Medical University, Yantai, China.
Aging Cell. 2025 Aug;24(8):e70115. doi: 10.1111/acel.70115. Epub 2025 May 26.
The activation of glycogen synthase kinase 3β (GSK-3β) and the deterioration of spatial memory represent prominent pathological and clinical manifestations of Alzheimer's disease (AD). Nevertheless, the precise intrinsic mechanisms linking these pathological features remain poorly elucidated. In this study, we identified significant upregulation of GSK-3β activity in inhibitory interneurons within the hippocampal dentate gyrus (DG) of 3×Tg-AD mice. Subsequent investigations demonstrated that targeted overexpression of GSK-3β in these interneurons triggered aberrant activation of neural stem cells (NSCs), culminating in apoptotic cell death and consequent deficits in adult hippocampal neurogenesis (AHN). Utilizing in vivo fiber-optic recording techniques, we further established that GSK-3β overexpression in DG inhibitory interneurons elicited hyperactivation of excitatory neurons, thereby disrupting the excitation-inhibition (E/I) balance within the DG circuitry. Notably, these pathological alterations were ameliorated through chemogenetic suppression of excitatory neuronal activity. Mechanistically, we determined that impaired GABAergic transmission, characterized by reduced GABA release in the DG region, underlies these observed effects. Pharmacological intervention with GABA receptor agonists effectively rescued AHN impairment and attenuated spatial cognitive deficits. Collectively, these findings demonstrate that GSK-3β overexpression in GABAergic interneurons compromises AHN and promotes NSC apoptosis via disruption of GABAergic signaling, while pharmacological potentiation of GABAergic transmission exerts neuroprotective effects. This study elucidates a previously unrecognized mechanism contributing to AHN impairment in AD and identifies a promising therapeutic target for pro-neurogenic strategies.
糖原合酶激酶3β（GSK-3β）的激活以及空间记忆的衰退是阿尔茨海默病（AD）突出的病理和临床表现。然而，将这些病理特征联系起来的精确内在机制仍不清楚。在本研究中，我们发现3×Tg-AD小鼠海马齿状回（DG）内抑制性中间神经元中GSK-3β活性显著上调。随后的研究表明，这些中间神经元中GSK-3β的靶向过表达引发神经干细胞（NSC）的异常激活，最终导致细胞凋亡和成年海马神经发生（AHN）缺陷。利用体内光纤记录技术，我们进一步证实DG抑制性中间神经元中GSK-3β的过表达会引起兴奋性神经元的过度激活，从而破坏DG回路中的兴奋-抑制（E/I）平衡。值得注意的是，通过化学遗传学抑制兴奋性神经元活动，这些病理改变得到了改善。从机制上讲，我们确定观察到的这些效应的基础是DG区域GABA释放减少所表征的GABA能传递受损。用GABA受体激动剂进行药物干预有效挽救了AHN损伤并减轻了空间认知缺陷。总的来说，这些发现表明，GABA能中间神经元中GSK-3β的过表达通过破坏GABA能信号传导损害AHN并促进NSC凋亡，而GABA能传递的药物增强则发挥神经保护作用。本研究阐明了一种先前未被认识的导致AD中AHN损伤的机制，并确定了一种有前景的促神经发生策略的治疗靶点。
