ENDOCANNABINOIDS IN NEURODEGENERATIVE DISEASES

While the etiology of Alzheimer's disease (AD) is multifactorial and complex, results from epidemiological,clinical, and laboratory animal studies implicate traumatic brain injury (TBI) as an important risk factor for ADand dementia. However, the mechanisms by which TBI increases the risk of AD are largely unknown. Inparticular, there are no effective therapies to prevent or treat TBI-caused AD neuropathology and dementia.Accumulating evidence suggests that neuroinflammation following the primary injury plays a critical factor insecondary brain damage and subsequent neuropathological changes. Therefore, resolving neuroinflammationwill significantly reduce secondary brain damage and eventually prevent or reduce the incidence of TBI-induced AD-like neurodegenerative disease. Endogenous cannabinoids display anti-inflammatory andneuroprotective properties. During the current period of funding, we provided evidence that monoacylglycerollipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in thebrain, is likely a new therapeutic target for AD. Pharmacological inactivation of MAGL reduces neuropathologyand improves synaptic plasticity and memory formation in animal models of both TBI and AD. However, we donot know whether genetic disruption of MAGL will yield beneficial effects similar to those followingpharmacological inhibition of MAGL in TBI. In addition, there is a gap in our knowledge about the signalingpathways that mediate anti-inflammatory and neuroprotective effects produced by MAGL inhibition in TBI. Inthis competing renewal application, we propose to test our hypothesis that alleviation of TBI-induced AD-likeneuropathological changes by pharmacological or genetic disruption of MAGL is primarily mediated byenhancement of 2-AG signaling in astrocytes, which, in turn curbs neuroinflammation. Thus, the primaryobjective of the studies proposed in this application will use our established mouse model of repetitive mildclosed head injury to demonstrate that inhibition of 2-AG metabolism by pharmacological inhibition or geneticdisruption of MAGL ameliorates AD-like neuropathology, improves recovery of synaptic and cognitivefunctions, and halts disease progression and delineate the signaling pathways that mediate the beneficialeffects produced by MAGL inhibition. The results from this project may ultimately lead to development of anovel therapeutic intervention for TBI-induced AD-like neurodegenerative disease.