title: Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis.
abstract: Inflammation in the brain is a prominent feature in Alzheimer's disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study, we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1), and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated β-amyloid (Aβ)42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aβ42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.
authors.affiliation: Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.|Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Xinmin Street No 71, Changchun, 130000, China.
authors.forename: Mingqin
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.|Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Xiuzhe
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Hjorth
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schroeder
authors.affiliation: Department of Neurosciences and the Center on Aging, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden. Marianne.Schultzberg@ki.se.
authors.forename: Marianne
authors.initials: M
authors.lastname: Schultzberg
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects*; D010641:Phenotype; D011180:Postmortem Changes; D019311:Staurosporine / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D016229:Amyloid beta-Peptides; D008055:Lipids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019311:Staurosporine
keywords: Alzheimer; Human; Inflammation; Lipoxin; Maresin; Microglia; Neuroprotection; Omega-3; Resolvin; SPMs