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

Ying Wang; Xiang Zhang; Henrik Biverstål; Nicolas G Bazan; Shuai Tan; Nailin Li; Makiko Ohshima; Marianne Schultzberg; Xiaofei Li

doi:10.4103/NRR.NRR-D-23-01688

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

Neural Regen Res. 2025 Mar 1;20(3):873-886. doi: 10.4103/NRR.NRR-D-23-01688. Epub 2024 May 17.

Authors

Ying Wang^{1

2}, Xiang Zhang³, Henrik Biverstål⁴, Nicolas G Bazan⁵, Shuai Tan⁶, Nailin Li⁶, Makiko Ohshima¹, Marianne Schultzberg¹, Xiaofei Li¹

Affiliations

¹ Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
² Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin Province, China.
³ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
⁴ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
⁵ Neuroscience Center of Excellence, Louisiana State University, New Orleans, LA, USA.
⁶ Department of Medicine, Solna, Clinical Pharmacology Group, Karolinska University Hospital, Stockholm, Sweden.

Abstract

JOURNAL/nrgr/04.03/01300535-202503000-00031/figure1/v/2024-06-17T092413Z/r/image-tiff 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.

Grants and funding

Funding: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).