第四军医大学研究团队取得一项新突破。他们的研究显示，在阿尔茨海默病小鼠模型中，BIN1与Tau片段相互作用抑制TrkB信号内体循环。2025年6月18日，国际知名学术期刊《神经科学通报》发表了这一成果。

课题组证明桥接整合子1 （BIN1）与P301S和Tau N368-Tg母主题脑中的Tau片段N368相互作用，通过阻碍BDNF/TrkB早期内核体循环来抑制其信号传导。Tau N368-Tg小鼠海马区过表达BIN1可部分挽救BDNF/TrkB内体运输，减轻病理和行为缺陷。他们的研究结果表明，由Tau N368-BIN1相互作用介导的早期内体通路功能障碍会损害BDNF信号，导致AD相关的病理和行为功能障碍。

据了解，BDNF/TrkB受体信号的缺陷导致天冬酰胺内肽酶活性增加，天冬酰胺内肽酶在N368残基处切割Tau蛋白，促进Tau蛋白的过度磷酸化和聚集，从而导致阿尔茨海默病（AD）的神经元功能障碍。然而，Tau N368是否抑制BDNF/TrkB信号通路仍然知之甚少。先前的研究表明，BDNF/TrkB复合物的内化，导致信号内体，是协调神经元存活和突触可塑性所必需的。

附：英文原文

Title: BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer’s Disease

Author: Wei, Yanuo, Xi, Ye, Li, Hui, Zhang, Xingxing, Wang, Yu, Li, Yunpeng, Fang, Ronghao, Xiang, Jie, Wu, Shengxi

Issue&Volume: 2025-06-18

Abstract: Deficits in BDNF/TrkB receptor signaling lead to increased asparagine endopeptidase activity, which cleaves Tau at the N368 residue to promote Tau hyperphosphorylation and aggregation, thereby contributing to neuronal dysfunction in Alzheimer’s disease (AD). However, whether Tau N368 inhibits the BDNF/TrkB signaling pathway remains poorly understood. Previous studies have shown that the internalization of the BDNF/TrkB complex, which leads to signaling endosomes, is necessary for coordinating neuronal survival and synaptic plasticity. Here, we demonstrate that Bridging Integrator 1 (BIN1) interacts with the Tau fragment N368 in P301S and Tau N368-Tg mouse brains, inhibiting BDNF/TrkB signaling by obstructing their early-endosome recycling. Overexpression of BIN1 in the hippocampus of Tau N368-Tg mice partially rescues BDNF/TrkB endosome transport and alleviates pathological and behavioral defects. Our findings suggest that dysfunction of the early-endosome pathway mediated by the Tau N368-BIN1 interaction impairs BDNF signaling, contributing to AD-associated pathological and behavioral dysfunction.

DOI: 10.1007/s12264-025-01435-y

Source: https://link.springer.com/article/10.1007/s12264-025-01435-y