Title

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

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