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今日快三开奖结果广西:Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies
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BDNF is important in neuronal survival and synaptic plasticity. BDNF level reduction in Alzheimer’s disease (AD) is well documented, but it remains unclear whether BDNF deficiency contributes to AD pathology. We show that BDNF deprivation provokes asparagine endopeptidase (AEP) activation via reducing δ-secretase (AEP) T322 phosphorylation by Akt and subsequently cleaves Tau at N368 residue and enhances its binding with TrkB receptors, blocking the neurotrophic signals. Our data demonstrate that AEP-cleaved Tau N368 interacting with TrkB might account for BDNF reduction-triggered AD 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.
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Author contributions: J.X. and K.Y. designed research; J.X., Z.-H.W., E.H.A., X.L., F.P.M., and I.M.S. performed research; J.X., S.-P.Y., G.J., S.W., and K.Y. analyzed data; and J.X. and K.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901348116/-/DCSupplemental.
Published under the PNAS license.