Inhibition of Exosome Release Alleviates Cognitive Impairment After Repetitive Mild Traumatic Brain Injury.

Tianpeng Hu,Jing Zhao,Lu Wang,Fanglian Chen,Qiang Liu,Meimei Li,Ping Lei,Dong Wang,Shishuang Zhang,Dai Li,Xiangyang Xiong,Zhaoli Han,Zhenyu Yin,Mengtian Guo,Lu Cheng

doi:10.3389/fncel.2022.832140

Abstract

BackgroundRepetitive mild traumatic brain injury (rmTBI) is closely associated with chronic traumatic encephalopathy (CTE). Neuroinflammation and neuropathological protein accumulation are key links to CTE progression. Exosomes play important roles in neuroinflammation and neuropathological protein accumulation and spread. Here, we explored the role of brain-derived exosomes (BDEs) in mice with rmTBI and how the inhibition of BDE release contributes to neuroprotection.MethodsGW4869 was used to inhibit exosome release, and behavioural tests, PET/CT and western blotting were conducted to explore the impact of this inhibition from different perspectives. We further evaluated cytokine expression by Luminex and microglial activation by immunofluorescence in mice with rmTBI after exosome release inhibition.ResultsInhibition of BDE release reversed cognitive impairment in mice with rmTBI, enhanced glucose uptake and decreased neuropathological protein expression. Inhibition of BDE release also changed cytokine production trends and enhanced microglial proliferation.ConclusionIn this study, we found that BDEs are key factor in cognitive impairment in mice with rmTBI and that microglia are the main target of BDEs. Thus, inhibition of exosome release may be a new strategy for improving CTE prognoses.

Highlights

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide (Rubiano et al, 2015; Jiang et al, 2019)
We measured the exosome quantity of mice with Repetitive mild traumatic brain injury (rmTBI) and found that there were no significant differences in particle numbers in mouse brains between the Sham group and rmTBI group; this finding suggested that the cargo carried by exosomes, but not the exosomes themselves, function during the process of rmTBI
positron emission tomography computed tomography (PET/CT) imaging of mice with rmTBI showed that one injection of GW4869 slightly enhanced the cerebral extraction of glucose in mice with rmTBI, which suggested that the inhibition of exosome secretion could improve the metabolism of mice with rmTBI

Summary

Introduction

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide (Rubiano et al, 2015; Jiang et al, 2019). Repetitive mild traumatic brain injury (rmTBI) has been shown to be closely associated with the development of chronic traumatic encephalopathy (CTE) in many studies (Smith et al, 2013; Wilson et al, 2017; Iverson et al, 2019). The rodent models used by various research groups are not the same in terms of many aspects such as injury interval, number of impacts and severity of injury (Turner et al, 2015).The impact acceleration (I/A) model, as a classic TBI damage model, was developed to stimulate mild, moderate, and severe TBI by using different weights and the velocity of impact to cause different degrees of damage (Yan et al, 2013; Hellewell et al, 2016). Repetitive mild traumatic brain injury (rmTBI) is closely associated with chronic traumatic encephalopathy (CTE). We explored the role of brain-derived exosomes (BDEs) in mice with rmTBI and how the inhibition of BDE release contributes to neuroprotection

Methods

Results

Conclusion