Endocannabinoids in neurodegenerative diseases - 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.