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, 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.
Neuroscience Research Unit, Pfizer Global Research and Development, Groton, CT 06340, USA.
Justin R
JR
Piro
Daniel I
DI
Benjamin
James M
JM
Duerr
YeQing
Y
Pi
Cathleen
C
Gonzales
Kathleen M
KM
Wood
Joel W
JW
Schwartz
Daniel K
DK
Nomura
Tarek A
TA
Samad
D000544:Alzheimer Disease / Q000150:complications / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism*; D063388:Endocannabinoids / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D017353:Gene Deletion; D005911:Gliosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D058225:Plaque, Amyloid / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism; D012995:Solubility
D016229:Amyloid beta-Peptides; D015777:Eicosanoids; D063388:Endocannabinoids; D053764:Presenilin-1; D008994:Monoacylglycerol Lipases