A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease
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, in...
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Published in | Cell reports (Cambridge) Vol. 1; no. 6; pp. 617 - 623 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
28.06.2012
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids 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 β 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 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.
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► Monoacylglycerol lipase (MAGL) is a major contributor to brain arachidonic acid pools ► MAGL mutation decreases neuroinflammation and amyloid β in Alzheimer's disease mouse ► MAGL blockade recapitulates brain prostaglandin and cytokine-lowering effects ► MAGL inhibitors may be a next-generation strategy for combating Alzheimer's disease
Nomura, Samad, and colleagues find that blockade of monoacylglycerol lipase (MAGL) reduces hallmarks of Alzheimer's disease (AD) such as neuroinflammation and accumulation of amyloid β in an AD mouse model. These changes are modulated by decreasing arachidonic acid levels in the brain that, in turn, lower the production of proinflammatory eicosanoids and cytokines. The development of MAGL inhibitors may therefore represent a potential therapeutic approach toward the treatment of AD. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2012.05.001 |