P75NTR blockading inhibits Trem2+ M1 phenotype microglia activation and myelin damage following mild traumatic brain injury

Xu Li¹Zhen Xu²Jing Fang²Hua-Dong Huang^3*

• ¹The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
• ²Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China
• ³Youjiang Medical University for Nationalities, Baise, China

The pathological basis underlying mild traumatic brain injury (mTBI)-induced long-term cognitive impairment is less understood. It is supposed that mTBI induces residential microglia activation rather than peripheral leukocyte infiltration to promote neuroinflammation, thus triggering myelin damage as well as the following cognitive impairment. The transformation of microglia towards pro-inflammatory (M1 type) or anti-inflammatory (M2 type) is critical for restraining cerebral inflammatory response to acute or chronic insults. Except for classical M1-and M2-like phenotypes, a specific subgroup of microglia, which is referred as Disease-associated microglia(DAM) and its transition is regulated by Triggering Receptor Expressed On Myeloid Cells 2(Trem2), is demonstrated to play critical roles in neurodegenerative diseases which sharing some similar pathological procedures with mTBI. The expression and function of p75 neurotrophin receptor (p75NTR) in microglia are varying depending on the type and severity of specific pathological stimuli. In current study, we examined whether peripheral leukocyte infiltrated into brains after mTBI by using a CX3C-chemokine receptor 1(Cx3cr1) and chemokine receptor 2 (Ccr2) double transgenic reporter mouse and whether M1-or M2-like phenotype microglia after mTBI showed DAM character by checking their Trem2 expression. Then we explored the expression of p75NTR in M1-and M2-like phenotype microglia after mTBI and its modulating effects on the activation of Trem2 positive M1-and M2-like phenotype microglia, neuroinflammatory reaction, myelin damage as well as the cognitive performances. We found most of the activated residential microglia after mTBI were Trem2 positive and p75NTR expression was significantly elevated in Trem2-positive M1-type microglia post-mTBI, correlating with increased pro-inflammatory cytokine release, demyelination and cognitive deficits. Pharmacological blockade of p75NTR using the antagonist TAT-Pep5 suppressed M1 microglial activation, reduced neuroinflammation, and restored myelin integrity, leading to marked improvements in cognitive function. Mechanistically, p75NTR exhibited a cell-type-specific regulatory role in neuroinflammatory responses, potentially through interacting with Trem2 to modulate DAM like microglia activation. These findings highlight p75NTR as a key mediator of mTBI-induced neuropathology and propose its inhibition as a novel therapeutic strategy to mitigate secondary neuroinflammation and cognitive decline.