| First Author | Wang ZH | Year | 2019 |
| Journal | Cell Rep | Volume | 28 |
| Issue | 3 | Pages | 655-669.e5 |
| PubMed ID | 31315045 | Mgi Jnum | J:288512 |
| Mgi Id | MGI:6432215 | Doi | 10.1016/j.celrep.2019.06.054 |
| Citation | Wang ZH, et al. (2019) Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates delta-Secretase by Upregulating C/EBPbeta in Alzheimer's Disease. Cell Rep 28(3):655-669.e5 |
| abstractText | 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/EBPbeta. This, in turn, results in increased expression of delta-secretase, leading to both APP and Tau fragmentation by delta-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPbeta, or the delta-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/EBPbeta, and delta-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPbeta upregulation, delta-secretase activity, and Abeta and Tau alterations in murine brains. |
