Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease
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.
Alzheimer’s diesase, BDNF, C/EBPβ, JAK2/STAT3, neuroinflammation, δ-secretase
Medical Subject Headings
Alzheimer Disease (enzymology, genetics, metabolism); Amyloid Precursor Protein Secretases (antagonists & inhibitors, genetics, metabolism); Amyloid beta-Protein Precursor (metabolism); Animals; Brain-Derived Neurotrophic Factor (genetics, metabolism); CCAAT-Enhancer-Binding Protein-beta (genetics, metabolism); Cognitive Dysfunction (genetics, metabolism); Cytokines (metabolism); Hippocampus (enzymology, metabolism, ultrastructure); Humans; Inflammation (genetics, metabolism); Janus Kinase 2 (metabolism); Membrane Glycoproteins (genetics, metabolism); Mice; Mice, Knockout; Neuronal Plasticity (genetics, physiology); Protein-Tyrosine Kinases (genetics, metabolism); Receptor, trkB (genetics, metabolism); STAT3 Transcription Factor (genetics, metabolism); Up-Regulation; tau Proteins (metabolism)
Digital Object Identifier (DOI)
Wang, Zhi-Hao; Xiang, Jie; Liu, Xia; Yu, Shan Ping; Manfredsson, Fredric P.; Sandoval, Ivette M.; Wu, Shengxi; Wang, Jian-Zhi; and Ye, Keqiang, "Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease" (2019). Translational Neuroscience. 1411.