A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease
Monday, Oct 15, 2012, 2:45 PM - 3:00 PM
*J. R. PIRO
, D. I. BENJAMIN
, J. M. DUERR
, Y. PI
, C. GONZALES
, K. M. WOOD
, J. W. SCHWARTZ
, D. K. NOMURA
, T. A. SAMAD
Pfizer Inc, Groton, CT;
Nutritional Sci. and Toxicology, Univ. of California Berkeley, Berkeley, CA
Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer’s disease (AD). The exact interplay between AD markers such as amyloid beta deposition and neuroinflammation is poorly understood. A major unanswered question is whether anti-inflammatory approaches can be used to treat AD. Endocannabinoids (ECs) are a class of lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes 2-AG to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins.
In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid beta [[unable to display character: ]]levels and plaques, in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a heretofore unrecognized role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology, and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.
[Authors]. [Abstract Title]. Program No. XXX.XX. 2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2012. Online.
2012 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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