Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 18, Pages 9094-9102Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1901348116
Keywords
AEP; Tau N368; BDNF deprivation; Tauopathy; Alzheimer's disease
Categories
Funding
- Alzheimer's Disease Research Center at Emory University
- National Institute on Aging/National Institutes of Health [RFO1 AG051538]
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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 delta-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 delta-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 delta-secretase in AD.
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