Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease.
Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease.
复制标题
单酰基甘油脂肪酶是阿尔茨海默氏病的治疗靶标。
DOI：
10.1016/j.celrep.2012.09.030
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发表时间：
2012-11-29
期刊：
影响因子：
8.8
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Chen R;Zhang J;Wu Y;Wang D;Feng G;Tang YP;Teng Z;Chen C
阿尔茨海默病(AD)是老年人痴呆症最常见的原因。目前还没有有效的药物来预防和治疗AD并阻止疾病的进展。单酰基甘油脂肪酶(MAGL)是脑内代谢内源性大麻素-2-花生四烯基甘油的主要酶。我们在这里表明，在AD小鼠模型中，MAGL的失活强烈地抑制了β-淀粉样蛋白(Aβ)的产生和积累，并与β位点淀粉样前体蛋白裂解酶1(BACE1)的表达减少有关。抑制MAGL还可预防神经炎症，减少神经退行性变，维持海马突触结构和功能的完整性，并改善AD动物的长期突触可塑性和空间学习记忆。虽然MAGL抑制作用的分子机制尚不清楚，但我们的结果表明，MAGL调节内源性大麻素和前列腺素信号转导，参与了AD的发病机制和神经病理，因此是防治AD的一个有前途的治疗靶点。
Alzheimer’s disease (AD) is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL) is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ) associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning and memory in AD animals. While the molecular mechanisms underlying MAGL inhibition-produced beneficial effects remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD and thus is a promising therapeutic target for the prevention and treatment of AD.