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

• Type of Material: Article
• Authors: Zhihao Wang, Emory University; Jie Xiang, Emory University; Xia Liu, Emory University; Shan Ping Yu, Emory University; Fredric P. Manfredsson, Michigan State University; Ivette M. Sandoval, Michigan State University; Shengxi Wu, Fourth Military Medical University; Keqiang Ye, Emory University
• Language: English
• Date: 2019-07-16
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2019.06.054
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 28
• Issue: 3
• Start Page: 655
• End Page: +
• Grant/Funding Information: This work was supported by an NIH grant (NIA RF1 AG051538) to K.Y.; Additional support was provided by the Emory Neuroscience NINDS Core Facilities (P30NS055077).; This work was also partially supported by the China Postdoctoral Science Foundation (2016M590695 and 2017T100558) to Z.-H.W.; Further support was provided by the Georgia Clinical & Translational Science Alliance of the NIH under award number UL1TR002378.; This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.
• Keywords: Cell Biology; PROTEIN SET; MEMORY; Science & Technology; DELETION; CELLS; BDNF; INHIBITION; Life Sciences & Biomedicine; PATHWAY; MODEL; BRAIN; TAU
• Research Categories: Health Sciences, Pathology; Biology, Cell; Health Sciences, Medicine and Surgery

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.