A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice

Jianhao Wang; Hang Yu; Xiang Li; Fang Li; Hongyu Chen; Xi Zhang; Yamei Wang; Ruifeng Xu; Feng Gao; Jiabei Wang; Pai Liu; Yuke Shi; Dongdong Qin; Yiyi Li; Songyan Liu; Shuai Ding; Xin-Ya Gao; Zhi-Hao Wang

doi:10.1016/j.bbi.2024.03.048

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice

Brain Behav Immun. 2024 Mar 29:119:56-83. doi: 10.1016/j.bbi.2024.03.048. Online ahead of print.

Authors

Jianhao Wang¹, Hang Yu¹, Xiang Li¹, Fang Li¹, Hongyu Chen¹, Xi Zhang¹, Yamei Wang¹, Ruifeng Xu², Feng Gao¹, Jiabei Wang¹, Pai Liu³, Yuke Shi¹, Dongdong Qin¹, Yiyi Li¹, Songyan Liu¹, Shuai Ding¹, Xin-Ya Gao⁴, Zhi-Hao Wang⁵

Affiliations

¹ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan 430060, China.
² Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan 430060, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100006, China.
³ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 USA.
⁴ Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China; Laboratory of Neurology, Henan Provincial People's Hospital, Zhengzhou 450003, China.
⁵ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: wangzh86@whu.edu.cn.

PMID: 38555992
DOI: 10.1016/j.bbi.2024.03.048

Abstract

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1β-C/EBPβ-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Keywords: Anxiety; Asparagine endopeptidase; Chronic stress; Depression; Neuroinflammation; TrkB.