Abstract：
:Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-β production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
Xia Y,Wang ZH,Liu P,Edgington-Mitchell L,Liu X,Wang XC,Ye Kdoi
10.1038/s41380-020-00863-8subject
Has Abstractpub_date
2020-08-11 00:00:00eissn
1359-4184issn
1476-5578pii
10.1038/s41380-020-00863-8pub_type
杂志文章abstract：:Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among other...
journal_title：Molecular psychiatry
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1038/sj.mp.4000965
更新日期：2002-01-01 00:00:00
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pub_type： 杂志文章,评审
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journal_title：Molecular psychiatry
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pub_type： 杂志文章
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pub_type： 杂志文章
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更新日期：2002-01-01 00:00:00
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pub_type： 杂志文章
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更新日期：2020-04-01 00:00:00
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pub_type： 杂志文章,评审
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