Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (3): 873-886.doi: 10.4103/NRR.NRR-D-23-01688

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Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Ying Wang1, 2, #, Xiang Zhang3, #, Henrik Biverstål4, Nicolas G. Bazan5, Shuai Tan6, Nailin Li6, Makiko Ohshima1, Marianne Schultzberg1, *, Xiaofei Li1, *   

  1. 1Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; 2Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin Province, China; 3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 4Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; 5Neuroscience Center of Excellence, Louisiana State University, New Orleans, LA, USA; 6Department of Medicine, Solna,   Clinical Pharmacology Group, Karolinska University Hospital, Stockholm, Sweden
  • Online:2025-03-15 Published:2024-06-26
  • Contact: Marianne Schultzberg, marianne.schultzberg@ki.se; Xiaofei Li, xiaofei.li@ki.se.
  • Supported by:
    This study was supported by the China Scholarship Council (to YW); the Swedish Research Council, No. 2018-02601 (to MS); the Alzheimer Foundation, No. AF-980695 (to MS); the Stockholm County Council, No. RS2020-0731 (to MS); the Foundation of Old Servants (to MS); the Gun and Bertil Stohne Foundation (to MS); the Åhlén Foundation, No. 233055 (to MS); The Swedish Fund for Research without Animal Experiments (to MS); the Swedish Dementia Foundation (to MS); and the Brain foundation, No. FO2022-0131 (to MS).

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Abstract: Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer’s disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer’s disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer’s disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer’s disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer’s disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer’s disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer’s disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer’s disease, highlighting its potential as a therapeutic target for Alzheimer’s disease.

Key words: Alzheimer’s disease, amyloid-β, maresin, microglia, monocyte, neuroinflammation, resolution, RNA-sequencing, specialized pro-resolving lipid mediator