Endocannabinoids in Neurodegenerative Diseases

总结 虽然阿尔茨海默病（AD）的病因是多因素和复杂的， 临床和实验室动物研究表明，创伤性脑损伤（TBI）是AD的重要危险因素 和痴呆症。然而，TBI增加AD风险的机制在很大程度上是未知的。在 特别地，没有有效的疗法来预防或治疗TBI引起的AD神经病理学和痴呆。 越来越多的证据表明，原发性损伤后的神经炎症在神经损伤中起着关键作用。 继发性脑损伤和随后的神经病理学变化。因此，解决神经炎症 将显著减少继发性脑损伤，并最终预防或减少TBI的发生率- 诱发AD样神经退行性疾病。内源性大麻素显示抗炎和 神经保护特性。在目前的资助期间，我们提供了证据表明，单酰基甘油 脂肪酶（MAGL），代谢内源性大麻素2-花生四烯酸甘油（2-AG）的关键酶， 脑内，可能是AD的一个新的治疗靶点。MAGL的药理学失活减少了神经病理学 并在TBI和AD的动物模型中改善突触可塑性和记忆形成。但我们 我不知道MAGL的遗传破坏是否会产生类似于以下的有益效果 MAGL在TBI中的药理学抑制。此外，我们对信号传递的了解还存在差距， TBI中MAGL抑制产生的抗炎和神经保护作用的介导途径。在 这种竞争性的更新应用，我们建议测试我们的假设，减轻TBI诱导的AD样 MAGL的药理学或遗传破坏引起的神经病理学变化主要由以下因素介导： 增强星形胶质细胞中的2-AG信号传导，从而抑制神经炎症。因此，主要 本申请中提出的研究目的将使用我们建立的重复性轻度 闭合性头部损伤，以证明通过药理学抑制或遗传学抑制2-AG代谢， MAGL的破坏改善AD样神经病理学，改善突触和认知功能的恢复， 功能，并阻止疾病进展，并描绘介导有益的 MAGL抑制产生的效果。该项目的结果可能最终导致开发一种 TBI诱导的AD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.