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

Authors

• 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

Recommended Citation

Wang, Zhi-Hao; Xiang, Jie; Liu, Xia; Yu, Shan Ping; Manfredsson, Fredric P.; Sandoval, Ivette M.; Wu, Shengxi; Wang, Jian-Zhi; and Ye, Keqiang, "Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease" (2019). Translational Neuroscience. 1411.
https://scholar.barrowneuro.org/neurobiology/1411