Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors.
Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors.
复制标题
通过抑制缺乏CB2受体的APP转基因小鼠中单酰甘油脂肪酶来缓解神经病理学。
DOI：
10.1007/s12035-017-0689-x
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发表时间：
2018-06
影响因子：
5.1
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Zhang J;Chen C
单酰基甘油脂酶（MAGL）是水解大脑中内源性大麻素2-花生四烯酸甘油酯（2-AG）的主要酶，其抑制在阿尔茨海默病（AD）的动物模型中产生深刻的抗炎和神经保护作用并改善突触和认知功能。然而，通过抑制2-AG代谢产生的有益作用的分子机制仍然不清楚。大麻素受体2型（CB 2 R）被认为是AD的治疗靶点。然而，在这里我们提供的证据表明，CB 2 R在改善AD神经病理学中不起作用，所述AD神经病理学是由5XFAD APP转基因小鼠（AD的动物模型）中MAGL的失活产生的。我们观察到，经选择性和有效的MAGL抑制剂JZL 184处理的CB 2 R缺失的APP转基因小鼠（TG-CB 2-KO）中APP和β-分泌酶的表达以及总Aβ和Aβ42的产生显著降低。MAGL的失活还减轻了TG-CB 2-KO小鼠中的神经炎症和神经变性。重要的是，用JZL 184治疗的TG-CB 2-KO小鼠仍然表现出空间学习和记忆的改善。此外，MAGL抑制防止了TG-CB 2-KO小鼠中重要突触蛋白表达的恶化。我们的研究结果表明，在AD模型动物中，CB 2 R不需要通过抑制2-AG代谢来改善神经病理学和预防认知下降。
Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear. The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD. We observed that expression of APP and β-secretase as well as production of total Aβ and Aβ42 were significantly reduced in APP transgenic mice lacking CB2R (TG-CB2-KO) treated with JZL184, a selective and potent inhibitor for MAGL. Inactivation of MAGL also alleviated neuroinflammation and neurodegeneration in TG-CB2-KO mice. Importantly, TG-CB2-KO mice treated with JZL184 still exhibited improvements in spatial learning and memory. In addition, MAGL inhibition prevented deterioration in expression of important synaptic proteins in TG-CB2-KO mice. Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals.
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影响因子：
9.3
作者：
Pihlaja R;Takkinen J;Eskola O;Vasara J;López-Picón FR;Haaparanta-Solin M;Rinne JO
通讯作者：
Rinne JO
影响因子：
64.5
作者：
Chen R;Zhang J;Fan N;Teng ZQ;Wu Y;Yang H;Tang YP;Sun H;Song Y;Chen C
通讯作者：
Chen C
DOI：
10.1016/j.pnpbp.2011.12.001
发表时间：
2012-07-02
影响因子：
5.6
作者：
Atwood, Brady K.;Straiker, Alex;Mackie, Ken
通讯作者：
Mackie, Ken
影响因子：
13.8
作者：
Hermanson, Daniel J.;Gamble-George, Joyonna C.;Marnett, Lawrence J.;Patel, Sachin
通讯作者：
Patel, Sachin
影响因子：
64.8
作者：
Panikashvili, D;Simeonidou, C;Shohami, E
通讯作者：
Shohami, E