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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712001258 |
| _version_ | 1811277104635969536 |
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| author | Justin R. Piro Daniel I. Benjamin James M. Duerr YeQing Pi Cathleen Gonzales Kathleen M. Wood Joel W. Schwartz Daniel K. Nomura Tarek A. Samad |
| author_facet | Justin R. Piro Daniel I. Benjamin James M. Duerr YeQing Pi Cathleen Gonzales Kathleen M. Wood Joel W. Schwartz Daniel K. Nomura Tarek A. Samad |
| author_sort | Justin R. Piro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T00:09:42Z |
| format | Article |
| id | doaj.art-f1b504b3e54442e2b36634e16abc72f7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T00:09:42Z |
| publishDate | 2012-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f1b504b3e54442e2b36634e16abc72f72022-12-22T03:11:08ZengElsevierCell Reports2211-12472012-06-011661762310.1016/j.celrep.2012.05.001A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's DiseaseJustin R. Piro0Daniel I. Benjamin1James M. Duerr2YeQing Pi3Cathleen Gonzales4Kathleen M. Wood5Joel W. Schwartz6Daniel K. Nomura7Tarek A. Samad8Neuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USAProgram in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USAProgram in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USANeuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USAAlthough 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.http://www.sciencedirect.com/science/article/pii/S2211124712001258 |
| spellingShingle | Justin R. Piro Daniel I. Benjamin James M. Duerr YeQing Pi Cathleen Gonzales Kathleen M. Wood Joel W. Schwartz Daniel K. Nomura Tarek A. Samad A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease Cell Reports |
| title | A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease |
| title_full | A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease |
| title_fullStr | A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease |
| title_full_unstemmed | A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease |
| title_short | A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease |
| title_sort | dysregulated endocannabinoid eicosanoid network supports pathogenesis in a mouse model of alzheimer s disease |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712001258 |
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