Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease

Cell Rep. 2019 Jul 16;28(3):655-669.e5. doi: 10.1016/j.celrep.2019.06.054.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism
  • Cytokines / metabolism
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Hippocampus / ultrastructure
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Janus Kinase 2 / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Up-Regulation
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Brain-Derived Neurotrophic Factor
  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • Cebpb protein, mouse
  • Cytokines
  • Membrane Glycoproteins
  • STAT3 Transcription Factor
  • tau Proteins
  • Ntrk2 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor, trkB
  • tropomyosin-related kinase-B, human
  • Janus Kinase 2
  • Amyloid Precursor Protein Secretases