Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer's disease pathologies
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.
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)
Proceedings of the National Academy of Sciences of the United States of America
Digital Object Identifier (DOI)
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.