Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer's disease pathologies
Document Type
Article
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.
Keywords
AEP, Alzheimer’s disease, BDNF deprivation, Tau N368, Tauopathy
Medical Subject Headings
Alzheimer Disease (metabolism, physiopathology); Amyloid Precursor Protein Secretases (metabolism); Amyloid beta-Peptides (metabolism); Animals; Brain (metabolism); Brain-Derived Neurotrophic Factor (metabolism); Cell Line; Cognition (physiology); Cognitive Dysfunction (metabolism); Cysteine Endopeptidases (metabolism); Female; Humans; Male; Mice; Mice, Inbred C57BL; Neurofibrillary Tangles (metabolism); Neurons (metabolism); Phosphorylation; Primary Cell Culture; Proto-Oncogene Proteins c-akt (metabolism); Receptor, trkB (antagonists & inhibitors, metabolism); Signal Transduction; tau Proteins (metabolism)
Publication Date
4-30-2019
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
E-ISSN
1091-6490
Volume
116
Issue
18
First Page
9094
Last Page
9102
PubMed ID
31004063
Digital Object Identifier (DOI)
10.1073/pnas.1901348116
Recommended Citation
Xiang, Jie; Wang, Zhi-Hao; Ahn, Eun Hee; Liu, Xia; Yu, Shan-Ping; Manfredsson, Fredric P.; Sandoval, Ivette M.; Ju, Gong; Wu, Shengxi; and Ye, Keqiang, "Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer's disease pathologies" (2019). Translational Neuroscience. 2023.
https://scholar.barrowneuro.org/neurobiology/2023