Endocannabinoids in neurodegenerative diseases

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Summary Dementia affects millions of people in the United States. Alzheimer’s disease (AD) is one of the most common causes of dementia in elderly. However, there are no effective therapies currently available for preventing and treating AD or halting progression of the disease. Therefore, it is imperative to develop efficacious therapies for AD. 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 for modifying disease progression. Endocannabinoids are naturally occurring bioactive lipid mediators involved in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG), the most abundant endocannabinoid, displays profound anti-inflammatory and neuroprotective properties. Inhibition of 2-AG degradation by pharmacological inactivation of monoacylglycerol lipase (MAGL), the key enzyme that degrades 2-AG in the brain, has been shown to produce neuroprotective effects in AD, and thus MAGL has been proposed as a therapeutic target for AD. During the current funding period, we discovered that genetic inactivation of MAGL reduces neuropathology and averts synaptic and cognitive declines in an animal model of traumatic brain injury (TBI). Surprisingly, these neuroprotective effects result primarily from augmentation of 2-AG signaling in astrocytes, rather than in neurons, suggesting that the neuroprotective effects induced by inactivation of MAGL in TBI are through 2-AG-mediated cell type-specific resolution of neuroinflammation. In this competing renewal application, we propose to determine whether genetic inactivation of MAGL produces anti-inflammatory and neuroprotective effects in animal models of AD and whether the protective effects are also cell type-specific. To reach this goal, we will assess beta-amyloid (Aβ) and tau neuropathology, structural and functional plasticity of synapses, and cognitive function by cell type-specific inactivation of MAGL in animal models of AD and delineate the molecular mechanisms that contribute to the MAGL inactivation-produced neuroprotective effects in AD. The outcome of the proposed research will enable us to better development of efficacious therapies or to refine treatments for AD.