Wei Yanuo, Xi Ye, Li Hui, Zhang Xingxing, Wang Yu, Li Yunpeng, Fang Ronghao, Xiang Jie, Wu Shengxi
The Key Laboratory of Neural and Vascular Biology, Ministry of Education and Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, 050000, China.
Department of Neurobiology, Fourth Military Medical University, Xi'an, 710032, China.
Neurosci Bull. 2025 Jun 18. doi: 10.1007/s12264-025-01435-y.
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.
脑源性神经营养因子（BDNF）/酪氨酸激酶受体B（TrkB）信号通路的缺陷会导致天冬酰胺内肽酶活性增加，该酶会在N368残基处切割 Tau蛋白，从而促进 Tau蛋白的过度磷酸化和聚集，进而导致阿尔茨海默病（AD）中的神经元功能障碍。然而，Tau蛋白N368是否会抑制BDNF/TrkB信号通路仍知之甚少。先前的研究表明，BDNF/TrkB复合物的内化会导致信号内体的形成，这对于协调神经元存活和突触可塑性是必要的。在此，我们证明在P301S和 Tau N368转基因小鼠大脑中，衔接整合蛋白1（BIN1）与Tau片段N368相互作用，通过阻碍其早期内体循环来抑制BDNF/TrkB信号通路。在Tau N368转基因小鼠海马中过表达BIN1可部分挽救BDNF/TrkB内体转运，并减轻病理和行为缺陷。我们的研究结果表明，由Tau N368-BIN1相互作用介导的早期内体途径功能障碍会损害BDNF信号，导致与AD相关的病理和行为功能障碍。
