Axonal injury mediated by neuronal p75NTR/TRAF6/JNK pathway contributes to cognitive impairment after repetitive mTBI

Gang Liu; Meijun He; Chaoran Wu; Pin Lv; Hao Sun; Heng Wang; Xiaoyan Xin; Hong Liao

doi:10.1016/j.expneurol.2023.114618

Axonal injury mediated by neuronal p75NTR/TRAF6/JNK pathway contributes to cognitive impairment after repetitive mTBI

Exp Neurol. 2024 Feb:372:114618. doi: 10.1016/j.expneurol.2023.114618. Epub 2023 Nov 27.

Authors

Gang Liu¹, Meijun He¹, Chaoran Wu¹, Pin Lv², Hao Sun¹, Heng Wang¹, Xiaoyan Xin³, Hong Liao⁴

Affiliations

¹ New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
² Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
³ Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. Electronic address: radchestxxy@njglyy.com.
⁴ New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China. Electronic address: hliao@cpu.edu.cn.

PMID: 38029807
DOI: 10.1016/j.expneurol.2023.114618

Abstract

Repetitive mild traumatic brain injury (rmTBI) is one of the leading causes of cognitive disorders. The impairment of axonal integrity induced by rmTBI is speculated to underlie the progression of cognitive dysfunction. However, few studies have uncovered the cellular mechanism regulating axonal impairment. In this study, we showed that after rmTBI, the activation of neuronal p75NTR signaling contributes to abnormal axonal morphology and impaired axonal transport, which further leads to cognitive dysfunction in mice. By neuron-specific knockdown of p75NTR or treatment with p75NTR inhibitor LM11A-31, we observed better recovery of axonal integrity and cognitive function after brain trauma. Further analysis revealed that p75NTR relies on its adaptor protein TRAF6 to activate downstream signaling via TAK1 and JNK. Overall, our results provide novel insight into the role of neuronal p75NTR in axonal injury and suggest that p75NTR may be a promising target for cognitive function recovery after rmTBI.

Trial registration: ClinicalTrials.gov NCT03069014.

Keywords: Axonal injury; Cognitive impairment; p75NTR; rmTBI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axons
Brain Concussion* / complications
Cognitive Dysfunction* / etiology
Disease Models, Animal
MAP Kinase Signaling System
Mice
Mice, Inbred C57BL
TNF Receptor-Associated Factor 6

Substances

TNF Receptor-Associated Factor 6

Associated data

ClinicalTrials.gov/NCT03069014