| First Author | Zhang J | Year | 2018 |
| Journal | Mol Neurobiol | Volume | 55 |
| Issue | 6 | Pages | 4802-4810 |
| PubMed ID | 28733897 | Mgi Jnum | J:351769 |
| Mgi Id | MGI:7664246 | Doi | 10.1007/s12035-017-0689-x |
| Citation | Zhang J, et al. (2018) Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors. Mol Neurobiol 55(6):4802-4810 |
| abstractText | 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 beta-secretase as well as production of total Abeta and Abeta42 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. |
