Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Brain. 2022 Mar 29;145(1):179-193. doi: 10.1093/brain/awab310.
Traumatic brain injury is an important risk factor for development of Alzheimer's disease and dementia. Unfortunately, no effective therapies are currently available for prevention and treatment of the traumatic brain injury-induced Alzheimer's disease-like neurodegenerative disease. This is largely due to our limited understanding of the mechanisms underlying traumatic brain injury-induced neuropathology. Previous studies showed that pharmacological inhibition of monoacylglycerol lipase, a key enzyme degrading the endocannabinoid 2-arachidonoylglycerol, attenuates traumatic brain injury-induced neuropathology. However, the mechanism responsible for the neuroprotective effects produced by inhibition of monoacylglycerol lipase in traumatic brain injury remains unclear. Here we first show that genetic deletion of monoacylglycerol lipase reduces neuropathology and averts synaptic and cognitive declines in mice exposed to repeated mild closed head injury. Surprisingly, these neuroprotective effects result primarily from inhibition of 2-arachidonoylglycerol metabolism in astrocytes, rather than in neurons. Single-cell RNA-sequencing data reveal that astrocytic monoacylglycerol lipase knockout mice display greater resilience to traumatic brain injury-induced changes in expression of genes associated with inflammation or maintenance of brain homeostasis in astrocytes and microglia. The monoacylglycerol lipase inactivation-produced neuroprotection is abrogated by deletion of the cannabinoid receptor-1 or by adeno-associated virus vector-mediated silencing of astrocytic peroxisome proliferator-activated receptor-γ. This is further supported by the fact that overexpression of peroxisome proliferator-activated receptor-γ in astrocytes prevents traumatic brain injury-induced neuropathology and impairments in spatial learning and memory. Our results reveal a previously undefined cell type-specific role of 2-arachidonoylglycerol metabolism and signalling pathways in traumatic brain injury-induced neuropathology, suggesting that enhanced 2-arachidonoylglycerol signalling in astrocytes is responsible for the monoacylglycerol lipase inactivation-produced alleviation of neuropathology and deficits in synaptic and cognitive functions in traumatic brain injury.
创伤性脑损伤是阿尔茨海默病和痴呆发展的重要危险因素。不幸的是，目前尚无有效的治疗方法可用于预防和治疗创伤性脑损伤引起的类似阿尔茨海默病的神经退行性疾病。这在很大程度上是由于我们对创伤性脑损伤引起的神经病理学的机制理解有限。以前的研究表明，抑制单酰基甘油脂肪酶（降解内源性大麻素 2-花生四烯酰甘油的关键酶）可减轻创伤性脑损伤引起的神经病理学。然而，抑制单酰基甘油脂肪酶在创伤性脑损伤中产生神经保护作用的机制尚不清楚。在这里，我们首先表明，单酰基甘油脂肪酶的基因缺失可减少病理学，并避免反复轻度闭合性颅脑损伤小鼠的突触和认知下降。令人惊讶的是，这些神经保护作用主要来自于星形胶质细胞中 2-花生四烯酰甘油代谢的抑制，而不是神经元。单细胞 RNA 测序数据显示，星形胶质细胞中单酰基甘油脂肪酶敲除小鼠对创伤性脑损伤引起的与炎症或星形胶质细胞和小胶质细胞中脑内稳态维持相关的基因表达变化具有更大的抵抗力。大麻素受体 1 缺失或腺相关病毒载体介导的星形胶质细胞过氧化物酶体增殖物激活受体-γ沉默可消除单酰基甘油脂肪酶失活引起的神经保护作用。这进一步得到了以下事实的支持：过表达星形胶质细胞中的过氧化物酶体增殖物激活受体-γ可防止创伤性脑损伤引起的神经病理学以及空间学习和记忆损伤。我们的结果揭示了 2-花生四烯酰甘油代谢和信号通路在创伤性脑损伤引起的神经病理学中以前未定义的细胞类型特异性作用，表明星形胶质细胞中增强的 2-花生四烯酰甘油信号传导是单酰基甘油脂肪酶失活引起的神经病理学减轻和创伤性脑损伤中突触和认知功能缺陷的原因。
