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

沉默星形细胞 MAGL 作为阿尔茨海默病的治疗方法

基本信息

批准号：
10633381
负责人：
CHU CHEN
金额：
$ 227.83万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633381
关键词：
2-arachidonylglycerol Acceleration Acute myocardial infarction Adverse effects Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Animal Diseases Animal Model Animals Anti-Inflammatory Agents Astrocytes Attenuated Brain Cells Cognitive Cognitive deficits Complex Dementia Deterioration Development Disease Disease Progression Early Intervention Elderly Endocannabinoids Enzymes Etiology Gene Expression Gene Silencing Genetic study Goals Hippocampus Human Impaired cognition Impairment Incidence Inflammation Inflammatory Injections Learning Lung Adenocarcinoma Mediating Memory Metabolism Microglia Modality Modification Monoacylglycerol Lipases Motor Mus Neurodegenerative Disorders Neurons Outcome Pathologic Processes Peripheral Persons Pharmacotherapy Physiological Processes Prevention Property Synapses Testing Therapeutic Tissues United States adeno-associated viral vector antagonist bone loss cell type cognitive function effective therapy efficacious intervention endogenous cannabinoid system gene therapy heart function improved inhibitor knock-down lipid mediator memory retention mouse model neuroinflammation neuropathology neuroprotection neurotoxic novel overexpression pharmacologic pre-clinical preclinical study prevent promoter restraint single-cell RNA sequencing synaptic function tau Proteins therapeutic target therapy outcome vector

项目摘要

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.

概括痴呆会影响美国数百万人。阿尔茨海默氏病（AD）是最常见的衰老中痴呆症的原因。但是，目前尚无有效的疗法可供预防和 AD的处理。因此，必须制定新颖有效的干预措施来预防和治疗AD或延迟疾病的进展。尽管AD的病因是多因素和复杂的，但积累的证据表明，神经炎症是神经退行性疾病的根本原因，包括广告。因此，解决神经炎症对于防止AD发展或延迟疾病至关重要进展。内源性大麻素是自然发生的脂质介质，参与多种生理和病理过程。 2-芳基烯丙基甘油（2-AG）是最丰富的内源性大麻素表现深刻的抗炎和神经保护特性，而其代谢产生促炎性和神经毒性。先前的研究表明，药物灭活对2AG代谢的抑制作用单酰基甘油脂肪酶（MAGL），一种关键酶降解2-AG的大脑，可降低AD神经病理学 AD的动物模型。这就是提议MAGL作为AD的治疗靶标。但是，最近的研究提供的证据表明，全球失活的MAGL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中的障碍，这表明 MAGL的药理学灭活可能不是实现理想治疗目标的最佳方法广告。相比之下，我们在初步研究中观察到了星形胶质细胞中MAGL的遗传失活，但不是在神经元中，减轻神经病理学并防止动物模型中的突触和认知恶化广告。这些结果表明，先前观察到的药物产生的神经保护作用 AD动物中MAGL失活的主要原因是限制星形胶质细胞中的2-Ag降解，而不是在神经元。这是我们假设在星形胶质细胞中特别有望在星形胶质细胞中敲除的理想和希望 AD的治疗将大大减少全球磁灭活造成的潜在不利影响 - 诱导神经元和其他周围细胞中2-AG代谢的破坏。但是，当前药物疗法没有能力靶向大脑中特定类型的细胞中的分子。所以，我们建议使用AAV矢量介导的MAGL在星形胶质细胞中的沉默来改善AD 神经病理学，预防，反向或停止在动物模型中的突触和认知功能中确定广告。这项临床前研究的预期结果最终将导致一种新颖有效的基因治疗对于广告。