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A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease.

ABSTRACT: 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 ? 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.

SUBMITTER: Piro JR

PROVIDER: S-EPMC3715876 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease.

Piro Justin R JR Benjamin Daniel I DI Duerr James M JM Pi YeQing Y Gonzales Cathleen C Wood Kathleen M KM Schwartz Joel W JW Nomura Daniel K DK Samad Tarek A TA

Cell reports 20120621 6

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) hy ...[more]

PMID: 22813736

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Project description:IntroductionAlzheimer's disease (AD) causes a decline in cognitive function that poses a significant hazard to human health. However, the exact pathogenesis of AD and effective treatment have both proven elusive. Circular RNAs (circRNAs), which were initially deemed as meaningless non-coding RNAs, have been shown to participate in a variety of physiological and pathological processes. However, the variations and characteristics of circRNAs are not fairly well understood during the occurrence and development of AD.MethodsIn this study, we performed RNA sequencing analyses, identified circRNA expression profiles, and explored the circRNA-associated competing endogenous RNA (ceRNA) relationship in the hippocampus of five familial AD (5 × FAD) mice with cognitive dysfunction.ResultsThe RNA sequencing results identified 34 dysregulated circRNAs in the hippocampus of 5 × FAD mice, including 17 upregulated and 17 downregulated circRNAs. The circRNA-miRNA interaction network for the dysregulated circRNAs was generated, and it was found to include 34 circRNAs and 711 miRNAs. Next, 2067 mRNAs potentially modulated by upregulated circRNA-interacting miRNAs and 2297 mRNAs potentially modulated by downregulated circRNA-interacting miRNAs were identified. Pathway enrichment analyses revealed that the circRNA-miRNA-mRNA network modulated AD development via multiple pathways, such as axon guidance, mitogen-activated protein kinase, and neurotrophin. The associated biological processes were mainly related to neuron projection development, cell morphogenesis, and head development. Their corresponding distributions were especially high in the axon, postsynapse, and neuronal body. We constructed a ceRNA network that included five circRNAs, four miRNAs, and 188 mRNAs. In this network, the differential expressions of three circRNAs (circRNA04655, circRNA00723, and circRNA01891), two miRNAs (miR-3470b and miR-6240), and 13 mRNAs (Vgll3, Nhsl2, Rab7, Tardbp, Vps33b, Fam107a, Tacr1, Ankrd40, Creb1, Snap23, Csnk1a1, Bmi1, and Bfar) in the hippocampus of 5 × FAD mice using qRT-PCR analyses were consistent with the RNA sequencing results. Another one circRNAs (circRNA00747) and two mRNAs (Zfp37 and Polr1e) had similar expression trends to the sequencing data, while circRNA03723 and Mapk10 had deviated expression trends to the sequencing data.ConclusionsIn conclusion, our study uncovered dysregulated circRNA expression profiles in the hippocampus of 5 × FAD mice, stretched comprehension of ceRNA biology, investigated the potential role of this ceRNA network in pathogenesis and progression, and identified potential biomarkers and therapeutic targets for AD.

Dataset Information

A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease.

Publications

A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease.

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