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Mol Neurobiol. 2016 May;53(4):2733-49. doi: 10.1007/s12035-015-9544-0. Epub 2015 Dec 9.

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis.

Author information

1
Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.
2
Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Xinmin Street No 71, Changchun, 130000, China.
3
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
4
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.
5
Department of Neurosciences and the Center on Aging, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA.
6
Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden. Marianne.Schultzberg@ki.se.

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.

KEYWORDS:

Alzheimer; Human; Inflammation; Lipoxin; Maresin; Microglia; Neuroprotection; Omega-3; Resolvin; SPMs

PMID:
26650044
PMCID:
PMC4824659
DOI:
10.1007/s12035-015-9544-0
[Indexed for MEDLINE]
Free PMC Article

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