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

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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.

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Acknowledgments

The authors are grateful for the support from the grants from The Swedish Research Council (22743, 22744); Swedish Brain Power; The Chinese Scholarship Council, P.R. China; The Knut and Alice Wallenberg Foundation; Karolinska Institutet research funds; Stiftelsen för Gamla Tjänarinnor; The Swedish Alzheimer Foundation; Gun och Bertil Stohnes Stiftelse; and Barmore Fund (MUSC). This work was also supported in part by the National Institutes of Health (P01GM095467 and GM038765 to C.N.S., and R21AG048631-01A1 to A.-C.G and M.S.).

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Authors and Affiliations

  1. Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden

    Mingqin Zhu, Xiuzhe Wang, Erik Hjorth, Lisa Schroeder & Marianne Schultzberg

  2. 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

    Romain A. Colas & Charles N. Serhan

  3. Department of Neurosciences and the Center on Aging, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Ann-Charlotte Granholm

  4. Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Xiuzhe Wang

  5. Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Xinmin Street No 71, Changchun, 130000, China

    Mingqin Zhu

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  1. Mingqin Zhu
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Correspondence to Marianne Schultzberg.

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C.N.S. has the following disclosures: as inventor on patents [resolvins] assigned to BWH and licensed to Resolvyx Pharmaceuticals, scientific founder of Resolvyx Pharmaceuticals with equity ownership in the company, and has interests reviewed and managed by the Brigham and Women’s Hospital and Partners Health Care in accordance with their conflict of interest policies.

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Fig. S1a–c

Actions of SPMs on differentiated human SH-SY5Y neuroblastoma cells. The cells were treated with 0–0.5 μM of the specialized pro-resolving mediators (SPMs) lipoxin A4 (LXA4), resolvin D1 (RvD1), maresin 1 (MaR1), and protectin DX (PDX). Treatment with SPMs was repeated at 6 and 24 h, and cell viability and cytotoxicity was assessed at 48 h by resazurin (a) and LDH (b) assay, respectively. As an index of cell survival the ratio between data from the resazurin and LDH assays was calculated (c), showing a significant effect of LXA4 and RvD1. The data were normalized to the average of each individual experiment and are presented as median ± non-outlier range (n = 7). Asterisk indicates p < 0.05 compared to vehicle treatment alone. K-W Kruskal–Wallis analysis of variance, LDH lactate dehydrogenase, SPMs specialized pro-resolving mediators (GIF 40 kb)

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Zhu, M., Wang, X., Hjorth, E. et al. Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis. Mol Neurobiol 53, 2733–2749 (2016). https://doi.org/10.1007/s12035-015-9544-0

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