Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates ?-Secretase by Upregulating C/EBP? in Alzheimer's Disease.

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/EBP?. This, in turn, results in increased expression of ?-secretase, leading to both APP and Tau fragmentation by ?-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBP?, or the ?-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/EBP?, and ?-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBP? upregulation, ?-secretase activity, and A? and Tau alterations in murine brains.

SUBMITTER: Wang ZH 

PROVIDER: S-EPMC6684282 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature