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Maresin 1 attenuates pro-inflammatory activation induced by ?-amyloid and stimulates its uptake.

ABSTRACT: Alzheimer's disease (AD) is the most common dementia, characterized by pathological accumulation of ?-amyloid (A?) and hyperphosphorylation of tau protein, together with a damaging chronic inflammation. The lack of effective treatments urgently warrants new therapeutic strategies. Resolution of inflammation, associated with beneficial and regenerative activities, is mediated by specialized pro-resolving lipid mediators (SPMs) including maresin 1 (MaR1). Decreased levels of MaR1 have been observed in AD brains. However, the pro-resolving role of MaR1 in AD has not been fully investigated. In the present study, human monocyte-derived microglia (MdM) and a differentiated human monocyte cell line (THP-1 cells) exposed to A? were used as models of AD neuroinflammation. We have studied the potential of MaR1 to inhibit pro-inflammatory activation of A? and assessed its ability to stimulate phagocytosis of A?₄₂ . MaR1 inhibited the A?₄₂ -induced increase in cytokine secretion and stimulated the uptake of A?₄₂ in both MdM and differentiated THP-1 cells. MaR1 was also found to decrease chemokine secretion and reduce the associated increase in the activation marker CD40. Activation of kinases involved in transduction of inflammation was not affected by MaR1, but the activity of nuclear factor (NF)-?B was decreased. Our data show that MaR1 exerts effects that indicate a pro-resolving role in the context of AD and thus presents itself as a potential therapeutic target for AD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7810927 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Maresin 1 attenuates pro-inflammatory activation induced by β-amyloid and stimulates its uptake.

Wang Ying Y Leppert Axel A Tan Shuai S van der Gaag Bram B Li Nailin N Schultzberg Marianne M Hjorth Erik E

Journal of cellular and molecular medicine 20201122 1

Alzheimer's disease (AD) is the most common dementia, characterized by pathological accumulation of β-amyloid (Aβ) and hyperphosphorylation of tau protein, together with a damaging chronic inflammation. The lack of effective treatments urgently warrants new therapeutic strategies. Resolution of inflammation, associated with beneficial and regenerative activities, is mediated by specialized pro-resolving lipid mediators (SPMs) including maresin 1 (MaR1). Decreased levels of MaR1 have been observe ...[more]

PMID: 33225628

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Project description:ObjectiveInflammation and its resolution are central to vascular injury and repair. Maresins comprise a new family of bioactive lipid mediators synthesized from docosahexaenoic acid, an ω-3 polyunsaturated fatty acid. They have been found to exert anti-inflammatory and pro-resolving responses in macrophages, neutrophils and bronchial epithelial cells and impart beneficial actions in murine models of peritonitis and colitis. We investigated the impact of maresin-1 (MaR1) on tumor necrosis factor alpha (TNF-α) induced inflammatory responses in human vascular endothelial (EC) and smooth muscle cells (VSMC).MethodsPrimary cultures of human saphenous vein EC and VSMC were employed. We tested the naturally occurring MaR1 as modulator of TNF-α effects, with examination of monocyte adhesion, oxidant stress, and intracellular inflammatory signaling pathways.ResultsMaR1 attenuated TNF-α induced monocyte adhesion and reactive oxygen species (ROS) generation in both EC and VSMC, associated with down-regulated expression (cell surface) of the adhesion molecule E-selectin (in EC) and NADPH-oxidases (NOX4, NOX1, NOX2). MaR1 attenuated TNF-α induced release of pro-inflammatory mediators by EC and VSMC. MaR1 caused an attenuation of TNF-α induced NF-κB activation in both cell types associated with inhibition of I-κ Kinase (IKK) phosphorylation, IκB-α degradation and nuclear translocation of the NF- κB p65 subunit. MaR1 also caused a time-dependent increase in intracellular cyclic AMP (cAMP) in both naive and TNF-α stimulated VSMC and EC.ConclusionsMaR1 has broad anti-inflammatory actions on EC and VSMC, which may be partly mediated through up-regulation of cAMP and down-regulation of the transcription factor NF-κB. The results suggest that the pro-resolving lipid mediator MaR1 exerts homeostatic actions on vascular cells that counteract pro-inflammatory signals. These findings may have direct relevance for acute and chronic states of vascular inflammation.

Project description:AimsThe accumulation and deposition of β-amyloid (Aβ) has always been considered a major pathological feature of Alzheimer's disease (AD). The latest and mainstream amyloid cascade hypothesis indicates that all the main pathological changes in AD are attributed to the accumulation of soluble Aβ. However, the exploration of therapeutic drugs for Aβ toxicity has progressed slowly. This study aims to investigate the protective effects of Icaritin on the Aβ-induced Drosophila AD model and its possible mechanism.MethodsTo identify the effects of Icaritin on AD, we constructed an excellent Drosophila AD model named Aβarc (arctic mutant Aβ42) Drosophila. Climbing ability, flight ability, and longevity were used to evaluate the effects of Icaritin on AD phenotypes. Aβarc was determined by immunostaining and ELISA. To identify the effects of Icaritin on oxidative stress, we performed the detection of ROS, hydrogen peroxide, MDA, SOD, catalase, GST, and Caspase-3. To identify the effects of Icaritin on energy metabolism, we performed the detection of ATP and lactate. Transcriptome analysis and qRT-PCR verifications were used to detect the genes directly involved in oxidative stress and energy metabolism. Mitochondrial structure and function were detected by an electron microscopy assay, a mitochondrial membrane potential assay, and a mitochondrial respiration assay.ResultsWe discovered that Icaritin almost completely rescues the climbing ability, flight ability, and longevity of Aβarc Drosophila. Aβarc was dramatically reduced by Icaritin treatment. We also found that Icaritin significantly reduces oxidative stress and greatly improves impaired energy metabolism. Importantly, transcriptome analysis and qRT-PCR verifications showed that many key genes, directly involved in oxidative stress and energy metabolism, are restored by Icaritin. Next, we found that Icaritin perfectly restores the integrity of mitochondrial structure and function damaged by Aβarc toxicity.ConclusionThis study suggested that Icaritin is a potential drug to deal with the toxicity of Aβarc, at least partially realized by restoring the mitochondria/oxidative stress/energy metabolism axis, and holds potential for translation to human AD.

Dataset Information

Maresin 1 attenuates pro-inflammatory activation induced by ?-amyloid and stimulates its uptake.

Publications

Maresin 1 attenuates pro-inflammatory activation induced by β-amyloid and stimulates its uptake.

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