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

总结 痴呆症影响着美国数百万人。阿尔茨海默病（AD）是最常见的疾病之一， 老年痴呆症的病因然而，目前还没有有效的治疗方法可用于预防， 治疗AD。因此，必须开发新的和有效的干预措施，以预防和 治疗AD或延缓疾病的进展。虽然AD的病因是多因素和复杂的， 累积的证据表明，神经炎症是神经退行性疾病的根本原因，包括 AD.因此，解决神经炎症对于预防AD的发展或延迟疾病至关重要 进展内源性大麻素是天然存在的脂质介质，参与多种生理和病理过程。 病理过程。2-花生四烯酰甘油（2-AG）是最丰富的内源性大麻素， 深刻的抗炎和神经保护特性，而其代谢产物是促炎和 神经毒性以前的研究表明，通过药理学灭活2-AG代谢抑制2-AG代谢， 单酰基甘油脂肪酶（MAGL），一种在大脑中降解2-AG的关键酶，可减轻AD患者的神经病理学。 AD动物模型因此，MAGL已被提议作为AD的治疗靶点。但最近的研究 提供的证据表明，MAGL的整体失活产生一些不利影响。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的药理学失活可能不是实现理想治疗目标的最佳方法， AD.相反，我们在我们的初步研究中观察到，星形胶质细胞中MAGL的遗传失活，而不是 在神经元中，减轻神经病理学，并防止突触和认知退化的动物模型， AD.这些结果表明，以前观察到的药理学产生的神经保护作用， AD动物中MAGL失活主要是由于星形胶质细胞中限制2-AG降解，而不是由于 神经元因此，我们假设特异性地在星形胶质细胞中敲除MAGL是一种理想且有前途的方法。 AD的治疗，这将极大地减少由整体MAGL失活引起的潜在不良反应- 诱导神经元和其他外周细胞中2-AG代谢的破坏。但目前的 药物疗法不具有靶向脑中特定类型细胞中的分子的能力。因此，我们认为， 我们建议使用AAV载体介导的星形胶质细胞中MAGL沉默的方式来改善AD 神经病理学，预防，逆转或停止突触和认知功能在动物模型中的恶化， AD.这项临床前研究的预期结果将最终导致一种新的和有效的基因治疗 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.