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

University Of Texas Hlth Science Center, San Antonio TX

Investigators

Linked publications, trials & patents

Abstract

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.