MAGL Inhibition in Prevention and Treatment of Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，以认知功能进行性恶化和记忆丧失为特征，并伴有广泛的神经元死亡。然而，目前还没有有效的药物来治愈或治疗阿尔茨海默病。内源性大麻素（eCBs）是内源性脂质信号介质，参与多种生理、药理学和病理过程，并能够通过激活大麻素受体（CB1R）来调节突触传递和可塑性，CB1R是大脑中主要表达的大麻素受体类型。越来越多的证据表明，2-花生四烯醇甘油（2- ag）是最丰富的eCB和CB1和CB2受体的完全激动剂，具有抗炎和神经保护作用。神经炎症是许多慢性神经和精神疾病的根源，并被认为是神经退行性疾病（如AD）的发病机制之一。然而，关于2-AG是否在β -淀粉样蛋白（AD的标志）和β -淀粉样蛋白诱导的突触和记忆缺陷的产生中起重要作用，我们知之甚少。该项目的目标是了解2-AG在AD的发展和神经病理学中的作用。在本探索性研究应用中，我们将在AD动物模型中验证我们的假设，即抑制单酰基甘油脂肪酶（MAGL）（一种水解2-AG的酶）能够阻止和减少A2的合成并减轻神经病理。目的1：验证内源性2-AG的升高能够减少或减缓APP转基因小鼠脑内β -淀粉样蛋白的产生和沉积的假设；目的2：验证MAGL抑制APP转基因动物神经炎症和预防神经退行性变的假说；目的3：验证MAGL抑制能够预防或挽救APP转基因小鼠长期突触可塑性和认知功能缺陷的假设。提出的应用将解决一个新颖而有趣的话题，即内源性2-AG在阿尔茨海默病的神经病理学中至关重要。该应用的结果不仅提供了实验证据，证明抑制MAGL能够减缓或减少β -淀粉样蛋白的合成和积累，改善β -淀粉样蛋白诱导的突触和记忆缺陷，预防神经退行性变，而且还表明通过抑制其水解或促进其合成来提高内源性2-AG的方法是新的有效的治疗干预措施。减轻或治疗阿尔茨海默病

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive function and loss of memory in association with widespread neuronal death. Currently, however, there are no effective medications to cure or treat AD. Endocannabinoids (eCBs) are endogenous lipid signaling mediators involved in a variety of physiological, pharmacological, and pathological processes and capable of modulating synaptic transmission and plasticity by activation of the cannabinoid receptor (CB1R), a predominantly expressed type of cannabinoid receptors in the brain. Growing evidence suggests that 2- arachidonoylglycerol (2-AG), the most abundant eCB and a full agonist for CB1 and CB2 receptors, renders anti-inflammatory and neuroprotective properties. Neuroinflammation is at the root of many chronic neurological and mental disorders and is believed to contribute to the pathogenesis of neurodegenerative diseases such as AD. However, little is known about whether 2-AG plays an important role in production of beta-amyloid, the hallmark of AD, and beta-amyloid-induced synaptic and memory deficits. The goal of the proposed project is to understand the role of 2-AG in development and neuropathology of AD. In this exploratory study application, we will test our hypothesis that inhibition of monoacylglycerol lipase (MAGL), an enzyme that hydrolyzes 2-AG, is able to prevent and reduce synthesis of A2 and alleviate neuropathology in an animal model of AD. This hypothesis will be tested by accomplishing three specific aims: Aim 1: To test the hypothesis that elevation of endogenous 2-AG is capable of reducing or slowing production and deposition of beta-amyloid in the brain of APP transgenic mice; Aim 2: To test the hypothesis that inhibition of MAGL is able to inhibit neuroinflammation and prevent neurodegeneration in APP transgenic animals; Aim 3: To test the hypothesis that inhibition of MAGL is able to prevent or rescue deficits in long-term synaptic plasticity and cognitive function in APP transgenic mice. The proposed application will tackle a novel and intriguing topic that endogenous 2-AG is crucial in neuropathology of AD. The results generated from this application will not only provide experimental evidence that inhibition of MAGL is capable of slowing or decreasing synthesis and accumulation of beta-amyloid, ameliorating beta-amyloid-induced synaptic and memory deficits, and preventing neurodegeneration, but also indicate that approaches that elevate endogenous 2-AG by inhibiting its hydrolysis or facilitating its synthesis are new efficacious therapeutic interventions for preventing, alleviating or treating Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposed application will tackle a novel and intriguing topic that naturally occurring 2-AG is crucial in neuropathology of AD. The results generated from this application will not only provide experimental evidence that inhibition of MAGL is capable of slowing or decreasing synthesis and accumulation of A2, ameliorating A2- induced synaptic and memory deficits, and preventing neurodegeneration, but also indicate that approaches that elevate endogenous 2-AG by inhibiting its hydrolysis or facilitating its synthesis are new efficacious therapeutic interventions for preventing, alleviating or treating Alzheimer's disease.