Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease

Zhi-Hao Wang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Jie Xiang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurobiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Xia Liu, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Shan Ping Yu, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Fredric P. Manfredsson, Department of Translational Science & Molecular Medicine, Michigan State University, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA.Follow
Ivette M. Sandoval, Department of Translational Science & Molecular Medicine, Michigan State University, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA.
Shengxi Wu, Department of Neurobiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Jian-Zhi Wang, Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Co-innovation Center of Neuroregeneration, Nantong, Jiangsu 226001, China. Electronic address: wangjz@mails.tjmu.edu.cn.
Keqiang Ye, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: kye@emory.edu.

Document Type

Article

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.

Keywords

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)

Publication Date

7-16-2019

Publication Title

Cell reports

E-ISSN

2211-1247

Volume

28

Issue

3

First Page

655

Last Page

669.e5

PubMed ID

31315045

Digital Object Identifier (DOI)

10.1016/j.celrep.2019.06.054

This document is currently not available here.

Share

COinS