Astrocyte-derived exosomes protect hippocampal neurons after traumatic brain injury by suppressing mitochondrial oxidative stress and apoptosis.

Wencheng Zheng,Hanwen Zhang,Ying Yang,Jun Hong,Wenqian Zhang

doi:10.18632/aging.203508

Abstract

In this study, we investigated the mechanisms through which astrocyte-derived exosomes (AS-Exos) alleviate traumatic brain injury (TBI)-induced neuronal defects in TBI model rats and mice. Treatment with AS-Exos alleviated neurobehavioral deficits, cognitive impairment, and brain edema in TBI rats. AS-Exos also significantly reduced neuronal cell loss and atrophy in the TBI rats. AS-Exos significantly reduced oxidative stress and mitochondrial H2O2 levels by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the hippocampal neurons of TBI rats. TUNEL-staining assays showed that AS-Exos significantly reduced TBI-induced neuronal apoptosis. Mechanistically, AS-Exos ameliorated oxidative stress by activating Nrf2/HO-1 signaling in the hippocampus of TBI rats. In addition, the neuroprotective effects of AS-Exos were abrogated in brain-specific Nrf2-knockout mice subjected to TBI. These findings demonstrate that AS-Exos protects against TBI-induced oxidative stress and neuronal apoptosis by activating Nrf2 signaling in both rat and mouse models.

Highlights

Traumatic brain injury (TBI) is related to high morbidity and mortality, and nearly 50 million TBI cases are reported worldwide each year [1, 2]
Western blot showed that exosome-specific markers such as CD9, CD63, and CD81 were highly expressed by the astrocyte-derived exosomes (AS-Exos) (Figure 1B)
TBI+AS-Exo group rats showed lower Modified neurological severity score (mNSS) values compared to the TBS group rats at 24 h, 48 h, and 7 d, but, mNSS values of Sham+AS-Exo group rats were similar to Sham rats (P > 0.05) (Figure 2A)

Summary

Introduction

Traumatic brain injury (TBI) is related to high morbidity and mortality, and nearly 50 million TBI cases are reported worldwide each year [1, 2]. TBI is classified as primary and secondary cerebral injuries based on the pathophysiological processes involved. Primary TBI is caused by direct mechanical force, whereas, secondary TBI involves pathophysiological processes such as oxidative stress, inflammation response, autophagy, neuronal death, and others [4,5,6]. Oxidative stress is caused by redox imbalance between reactive oxygen species (ROS) and the antioxidative defense systems in cells and tissues [7]. Mitochondrial dysfunction in neuronal cells results in generation of excessive ROS, which causes oxidative damage [9] and programmed neuronal cell death or apoptosis [10]. Current therapeutic interventions for patients with TBI are limited and include drugs that improve nervous functions by reducing oxidative stress and alleviating mitochondrial dysfunction [11]

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