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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.

总结