Abstract
BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer's disease (AD). However, exactly how BDNF/TrkB participates in AD pathology remains unclear. Here, we show that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPβ, or the δ-secretase enzymatic-dead C189S mutant. Inhibition of this pathological cascade can also rescue impaired synaptic plasticity and cognitive dysfunctions. Importantly, reduction in BDNF/TrkB neurotrophic signaling is inversely coupled with an increase in JAK2/STAT3, C/EBPβ, and δ-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPβ upregulation, δ-secretase activity, and Aβ and Tau alterations in murine brains.
Keywords:
Alzheimer’s diesase; BDNF; C/EBPβ; JAK2/STAT3; neuroinflammation; δ-secretase.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / enzymology
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism*
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism*
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Cognitive Dysfunction / genetics
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Cognitive Dysfunction / metabolism
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Cytokines / metabolism
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Hippocampus / enzymology
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Hippocampus / metabolism
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Hippocampus / ultrastructure
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Humans
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Inflammation / genetics
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Inflammation / metabolism
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Janus Kinase 2 / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Neuronal Plasticity / genetics
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Neuronal Plasticity / physiology
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Receptor, trkB / genetics
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Receptor, trkB / metabolism*
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Up-Regulation
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tau Proteins / metabolism
Substances
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Amyloid beta-Protein Precursor
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Brain-Derived Neurotrophic Factor
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CCAAT-Enhancer-Binding Protein-beta
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CEBPB protein, human
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Cebpb protein, mouse
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Cytokines
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Membrane Glycoproteins
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STAT3 Transcription Factor
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tau Proteins
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Ntrk2 protein, mouse
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Protein-Tyrosine Kinases
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Receptor, trkB
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tropomyosin-related kinase-B, human
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Janus Kinase 2
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Amyloid Precursor Protein Secretases