Differential Regulation of Resolution in Inflammation induced by Amyloid-β42 and Lipopolysaccharides in Human Microglia

Zhu, Mingqin; Wang, Xiuzhe; Schultzberg, Marianne; Hjorth, Erik

doi:10.3233/jad-141233

Cited by 39 publications

(39 citation statements)

References 268 publications

(307 reference statements)

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“…In vitro studies demonstrated production of PD1 in mixed human neuron-glia cell cultures [4], and our studies on the human microglia cell line (CHME-3) showed LXA 4 and RvD1 in the conditioned medium [38]. Immunohistochemical studies on human and murine brains have shown the occurrence of the biosynthetic enzymes 5-LOX and 15-LOX in neurons and glia [6,39–42].…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2015

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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, RvD1 and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated Aβ42-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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Section: Discussionmentioning

confidence: 91%

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

et al. 2015

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“…Upon binding to their specifi c receptors, SPMs downregulate proinfl ammatory signals and promote the healing process of the tissue ( 11 ). Recent studies have indicated that resolution of infl ammation is disturbed in AD ( 12,13 ) and AD-related models (14)(15)(16). Treatment with one of the SPMs, lipoxin A 4 (LXA 4 ), has been demonstrated to rescue synaptic loss and reduce AD-like pathologies in transgenic AD mouse models ( 17,18 ).…”

Section: Pbmc Preparation and Ex Vivo Experimentsmentioning

confidence: 99%

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study

Wang

Hjorth

Vedin

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org Many diseases of the brain display signs of infl ammation, including Alzheimer's disease (AD), the most common type of dementia. The association between infl ammation and AD is evidenced from many different disciplines of research. Postmortem studies have revealed increased levels of proinfl ammatory cytokines in the AD brain ( 1-3 ), particularly around the amyloid plaques, and further support is provided by analysis of clinical samples from AD patients, including elevated proinfl ammatory markers in cerebrospinal fl uid (CSF) ( 4 ) and plasma/serum ( 5-7 ) samples. Epidemiological studies have shown that longterm use of nonsteroidal anti-infl ammatory drugs (NSAIDs) confers reduced prevalence of AD ( 8 ). However, prospective clinical trials based on NSAIDs have not been successful in reducing the cognitive decline in AD ( 8, 9 ).Consumption of PUFAs, especially the n-3 FAs DHA and EPA, is well known for benefi cial effects in the regulation of infl ammation ( 10 ). PUFAs can modulate the infl ammatory response by changing cell membrane fl uidity and composition, leading to effects on the function of receptors, and the conductance of ion channels involved in immune activation. In recent years, the concept of resolution of infl ammation has received attention due to the discovery of specialized proresolving mediators (SPMs). SPMs are lipid mediators (LMs) derived from PUFAs and play a key role in resolution, in which the tissue is restored by removal of cellular and molecular debris, and regeneration/ Abstract Specialized proresolving mediators (SPMs) induce resolution of infl ammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their benefi cial effects. It is unknown whether supplementation with PUFAs infl uences the production of SPMs. Alzheimer's disease (AD) is associated with brain infl ammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-␤ 1-40 showed unchanged levels of the SPMs lipoxin A 4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

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“…Microglia, resident immune cells in the CNS, play critical roles in host defense and tissue repair in brain [2]. Once activation by LPS or b-amyloid, microglia cells release various inflammatory mediators such as TNF-a, IL-1b, NO, and PGE 2 [3,4]. These inflammatory mediators lead to neuronal damage and involved in the pathogenesis of neurodegenerative disease [5,6].…”

Section: Introductionmentioning

confidence: 99%

Linalool Inhibits LPS-Induced Inflammation in BV2 Microglia Cells by Activating Nrf2

Zhou

et al. 2015

Neurochem Res

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Linalool, a natural compound of the essential oils, has been reported to have anti-inflammatory effects. This study aimed to investigate the anti-inflammatory effects and mechanism of linalool in LPS-stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of linalool. The production of inflammatory mediators TNF-α, IL-1β, NO, and PGE2 as well as Nrf2, HO-1 expression were detected. Our results showed that linalool inhibited LPS-induced TNF-α, IL-1β, NO, and PGE2 production in a dose-dependent manner. Linalool also inhibited LPS-induced NF-κB activation. Treatment of linalool induced nuclear translocation of Nrf2 and expression of HO-1. In addition, our results showed that the anti-inflammatory effect of linalool was attenuated by transfection with Nrf2 siRNA. In conclusion, these results suggested that linalool inhibits LPS-induced inflammation in BV2 microglia cells by activating Nrf2/HO-1 signaling pathway.

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Differential Regulation of Resolution in Inflammation induced by Amyloid-β42 and Lipopolysaccharides in Human Microglia

Cited by 39 publications

References 268 publications

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

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

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study

Linalool Inhibits LPS-Induced Inflammation in BV2 Microglia Cells by Activating Nrf2

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