Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer's disease pathologies

• Type of Material: Article
• Authors: Jie Xiang, Fourth Military Medical University; Zhihao Wang, Emory University; Eun Hee Ahn, Emory University; Xia Liu, Emory University; Shan Ping Yu, Emory University; Fredric P. Manfredsson, Michigan State University; Ivette M. Sandoval, Michigan State University; Gong Ju, Fourth Military Medical University; Shenxi Wu, Fourth Military Medical University; Keqiang Ye, Emory University
• Language: English
• Date: 2019-04-30
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1901348116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 18
• Start Page: 9094
• End Page: 9102
• Grant/Funding Information: This work was supported by National Institute on Aging/National Institutes of Health Grant RFO1 AG051538 (to K.Y.).
• Keywords: TRANSCRIPT; FACTOR BDNF; Science & Technology - Other Topics; Tauopathy; Multidisciplinary Sciences; IN-VITRO; EXPRESSION; INHIBITION; Alzheimer's disease; BRAIN; Science & Technology; DOWN-REGULATION; MOUSE MODELS; Tau N368; DEFICITS; BDNF deprivation; AEP; TRAFFICKING
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

BDNF, an essential trophic factor implicated in synaptic plasticity and neuronal survival, is reduced in Alzheimer’s disease (AD). BDNF deficiency’s association with Tau pathology in AD is well documented. However, the molecular mechanisms accounting for these events remain incompletely understood. Here we show that BDNF deprivation triggers Tau proteolytic cleavage by activating δ-secretase [i.e., asparagine endopeptidase (AEP)], and the resultant Tau N368 fragment binds TrkB receptors and blocks its neurotrophic signals, inducing neuronal cell death. Knockout of BDNF or TrkB receptors provokes δ-secretase activation via reducing T322 phosphorylation by Akt and subsequent Tau N368 cleavage, inducing AD-like pathology and cognitive dysfunction, which can be restored by expression of uncleavable Tau N255A/N368A mutant. Blocking the Tau N368–TrkB complex using Tau repeat-domain 1 peptide reverses this pathology. Thus, our findings support that BDNF reduction mediates Tau pathology via activating δ-secretase in AD.