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

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