BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer’s Disease
Yanuo Wei1 · Ye Xi2 · Hui Li2 · Xingxing Zhang2 · Yu Wang2 · Yunpeng Li2 · Ronghao Fang2 · Jie Xiang2 · Shengxi Wu1,2
1 The Key Laboratory of Neural and Vascular Biology, Ministry of Education and Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050000, China
2 Department of Neurobiology, Fourth Military Medical University, Xi’an 710032, China
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.
Keywords
Tau N368; Bridging Integrator 1; Alzheimer’s Disease; Tau N368-Tg mouse; Hippocampus
