Silencing of astrocytic MAGL as a therapy for Alzheimer’s disease

摘要 痴呆症在美国影响着数百万人。阿尔茨海默病(AD)是最常见的 老年痴呆症的病因。然而，目前还没有有效的预防和治疗方法。 治疗阿尔茨海默病。因此，开发新的、有效的预防和预防措施势在必行。 治疗阿尔茨海默病或延缓疾病进展。虽然阿尔茨海默病的病因是多因素和复杂的， 越来越多的证据表明，神经炎症是神经退行性疾病的根本原因，包括 广告。因此，解决神经炎症对于预防AD的发展或延缓疾病是至关重要的 进步。内源性大麻素是一种天然存在的脂质介质，参与多种生理和 病理过程。2-花生四烯基甘油(2-AG)是最丰富的内源性大麻素 深刻的抗炎和神经保护作用，而它的代谢物是促炎和 神经毒性。先前的研究表明，通过药物失活来抑制2-AG的代谢 单酰基甘油脂肪酶(MAGL)是大脑中降解2-AG的关键酶，可减轻AD大鼠的神经病理 AD的动物模型。因此，MAGL被认为是治疗阿尔茨海默病的靶点。然而，最近的研究 提供了证据表明MAGL在全球范围内失活会产生一些不利影响。特别是，我们观察到 神经元中MAGL的选择性失活会导致学习和记忆障碍，这表明 MAGL的药物灭活可能不是实现理想治疗目标的最佳方法 广告。相反，我们在初步研究中观察到，在星形胶质细胞中，MAGL的遗传失活，但不是 在神经元中，减轻神经病理和防止突触和认知恶化的动物模型 广告。这些结果表明，先前观察到的药物所产生的神经保护作用 AD动物MAGL失活的主要原因是限制了星形胶质细胞中2-AG的降解，而不是 神经元。因此，我们假设在星形胶质细胞中特异地敲除MAGL是一种理想和有前途的方法。 治疗AD，这将极大地减少全球MAGL失活造成的潜在不良影响- 诱导神经元和其他外周细胞2-AG代谢中断。但是，当前 药物疗法没有能力针对大脑中特定类型的细胞中的分子。因此， 我们建议使用AAV载体介导的MAGL在星形胶质细胞中沉默的方式来改善AD 神经病理学，预防、逆转或阻止突触和认知功能的恶化 广告。这项临床前研究的预期结果将最终导致一种新的有效的基因疗法。 对于AD。

Summary Dementia affects millions of people in the United States. Alzheimer’s disease (AD) is one of the most common causes of dementia in aging. However, there are no effective therapies currently available for prevention and treatment of AD. Therefore, it is imperative to develop novel and efficacious interventions for preventing and treating AD or delaying progression of the disease. Although the etiology of AD is multifactorial and complex, accumulated evidence suggests that neuroinflammation is a root cause of neurodegenerative diseases, including AD. Hence, resolving neuroinflammation is crucial for preventing development of AD or delaying disease progression. Endocannabinoids are naturally occurring lipid mediators involved in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid displaying profound anti-inflammatory and neuroprotective properties, while its metabolites are proinflammatory and neurotoxic. Previous studies demonstrated that inhibition of 2-AG metabolism by pharmacological inactivation of monoacylglycerol lipase (MAGL), a key enzyme degrading 2-AG in the brain, reduces AD neuropathology in animal models of AD. Thus, MAGL has been proposed as a therapeutic target for AD. However, recent studies provided evidence that global inactivation of MAGL produces some adverse effects. In particular, we observed that selective inactivation of MAGL in neurons causes impairments in learning and memory, suggesting that pharmacological inactivation of MAGL may not be an optimal approach to achieve an ideal therapeutic goal for AD. In contrast, we observed in our preliminary studies that genetic inactivation of MAGL in astrocytes, but not in neurons, alleviates neuropathology and prevents synaptic and cognitive deteriorations in animal models of AD. These results indicate that previously observed neuroprotective effects produced by pharmacological inactivation of MAGL in AD animals result primarily from limiting 2-AG degradation in astrocytes, rather than in neurons. Thus, we hypothesize that knockdown of MAGL specifically in astrocytes is an ideal and promising therapy for AD, which will greatly minimizes potential adverse effects resulting from global MAGL inactivation- induced disruption of 2-AG metabolism in neurons and other peripheral cells. However, current pharmacotherapies do not have the capacity to target a molecule in a specific type of cells in the brain. Therefore, we propose to use a modality of AAV vector-mediated silencing of MAGL in astrocytes to ameliorate AD neuropathology, prevent, reverse or halt deterioration in synaptic and cognitive functions in animal models of AD. The expected outcome of this preclinical study will ultimately lead to a novel and efficacious gene therapy for AD.