Endocannabinoids in Neurodegenerative Diseases

摘要 虽然阿尔茨海默病(AD)的病因是多因素和复杂的，但由于流行病学， 临床和实验动物研究表明创伤性脑损伤(TBI)是AD的重要危险因素 和痴呆症。然而，脑外伤增加AD风险的机制在很大程度上尚不清楚。在……里面 特别是，目前还没有有效的治疗方法来预防或治疗脑外伤引起的阿尔茨海默病和痴呆。 越来越多的证据表明，原发性损伤后的神经炎症在 继发性脑损伤和随后的神经病理改变。因此，化解神经性炎症 将显著减少继发性脑损伤，并最终预防或降低脑损伤的发生率- 诱发类AD神经退行性疾病。内源性大麻素具有抗炎和抗炎作用 神经保护特性。在本供资期间，我们提供的证据表明，单甘油 脂肪酶(MAGL)是体内代谢内源性大麻素2-花生四烯基甘油(2-AG)的关键酶。 大脑，很可能是AD的新治疗靶点。MAGL的药理灭活可减轻神经病理 改善脑外伤和AD动物模型的突触可塑性和记忆形成。然而，我们有 不知道MAGL的基因破坏是否会产生类似于以下的有益效果 MAGL在脑外伤中的药理抑制作用。此外，我们对信号的了解也存在差距 介导MAGL抑制脑损伤后的抗炎和神经保护作用的途径。在……里面 这个相互竞争的续订应用程序，我们建议测试我们的假设，即脑损伤诱导的类AD的缓解 MAGL的药理或遗传破坏所致的神经病理改变主要是由 增强星形胶质细胞中的2-AG信号，进而抑制神经炎症。因此，主要的 本申请中提出的研究目标将使用我们建立的重复性轻度小鼠模型 闭合性颅脑损伤证明通过药物抑制或遗传抑制2-AG代谢 MAGL阻断可改善AD样神经病理，促进突触和认知功能的恢复 功能，阻止疾病的进展，并描绘出介导有益的信号通路 MAGL抑制产生的效果。这个项目的结果可能最终导致开发一种 脑外伤所致阿尔茨海默病样神经退行性疾病的新治疗干预。

Summary While the etiology of Alzheimer's disease (AD) is multifactorial and complex, results from epidemiological, clinical, and laboratory animal studies implicate traumatic brain injury (TBI) as an important risk factor for AD and dementia. However, the mechanisms by which TBI increases the risk of AD are largely unknown. In particular, there are no effective therapies to prevent or treat TBI-caused AD neuropathology and dementia. Accumulating evidence suggests that neuroinflammation following the primary injury plays a critical factor in secondary brain damage and subsequent neuropathological changes. Therefore, resolving neuroinflammation will significantly reduce secondary brain damage and eventually prevent or reduce the incidence of TBI- induced AD-like neurodegenerative disease. Endogenous cannabinoids display anti-inflammatory and neuroprotective properties. During the current period of funding, we provided evidence that monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is likely a new therapeutic target for AD. Pharmacological inactivation of MAGL reduces neuropathology and improves synaptic plasticity and memory formation in animal models of both TBI and AD. However, we do not know whether genetic disruption of MAGL will yield beneficial effects similar to those following pharmacological inhibition of MAGL in TBI. In addition, there is a gap in our knowledge about the signaling pathways that mediate anti-inflammatory and neuroprotective effects produced by MAGL inhibition in TBI. In this competing renewal application, we propose to test our hypothesis that alleviation of TBI-induced AD-like neuropathological changes by pharmacological or genetic disruption of MAGL is primarily mediated by enhancement of 2-AG signaling in astrocytes, which, in turn curbs neuroinflammation. Thus, the primary objective of the studies proposed in this application will use our established mouse model of repetitive mild closed head injury to demonstrate that inhibition of 2-AG metabolism by pharmacological inhibition or genetic disruption of MAGL ameliorates AD-like neuropathology, improves recovery of synaptic and cognitive functions, and halts disease progression and delineate the signaling pathways that mediate the beneficial effects produced by MAGL inhibition. The results from this project may ultimately lead to development of a novel therapeutic intervention for TBI-induced AD-like neurodegenerative disease.