Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury
Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury
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DOI：
10.1038/jcbfm.2014.216
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发表时间：
2015-03-01
影响因子：
6.3
通讯作者：
Chen, Chu
中科院分区：
文献类型：
--
作者：
Zhang, Jian;Teng, Zhaoqian;Chen, Chu
新出现的证据表明，在暴露于重复性创伤性脑损伤（TBI）的军事人员和接触性体育运动员中，发生慢性创伤性脑病（CTE）（一种进行性神经退行性疾病）的风险显著增加。不幸的是，目前还没有有效的药物来预防和治疗CTE。本研究表明，抑制单酰基甘油脂肪酶（MAGL）是大脑中代谢内源性大麻素2-花生四烯醇甘油（2-AG）的关键酶，可显著减少重复性轻度闭合性颅脑损伤（rmCHI）小鼠模型中cte样神经病理变化。抑制2-AG代谢可促进rmCHI后的神经系统恢复，降低促炎细胞因子、星形胶质细胞反应性、淀粉样蛋白前体蛋白和制造A β的酶的表达，以及A β的形成。重要的是，神经退行性变、TDP-43蛋白聚集和tau磷酸化，这些CTE的神经病理学标志，被MAGL失活显著抑制。此外，通过抑制2-AG代谢，暴露于rmCHI的动物可以恢复谷氨酸受体亚基表达的改变和基础突触传递、长期突触可塑性和空间学习记忆的损伤。我们的研究结果表明，MAGL抑制可以提高2-AG并降低大脑中2-AG代谢物前列腺素，这可能会导致CTE的新疗法。
Emerging evidence suggests that the risk of developing chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease, is significantly increased in military personnel and contact sports players who have been exposed to repetitive trauma brain injury (TBI). Unfortunately there are no effective medications currently available for prevention and treatment of CTE. Here we demonstrate that inhibition of monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, significantly reduced CTE-like neuropathologic changes in a mouse model of repetitive mild closed head injury (rmCHI). Inhibition of 2-AG metabolism promoted neurologic recovery following rmCHI and reduced proinflammatory cytokines, astroglial reactivity, expression of amyloid precursor protein and the enzymes that make A beta, as well as formation of A beta. Importantly, neurodegeneration, TDP-43 protein aggregation, and tau phosphorylation, which are the neuropathologic hallmarks of CTE, were significantly suppressed by MAGL inactivation. Furthermore, alterations in expression of glutamate receptor subunits and impairments in basal synaptic transmission, long-term synaptic plasticity, and spatial learning and memory were recovered by inhibition of 2-AG metabolism in animals exposed to rmCHI. Our results suggest that MAGL inhibition, which boosts 2-AG and reduces 2-AG metabolites prostaglandins in the brain, may lead to a new therapy for CTE.