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

作　　者：Ying Wang Xiang Zhang Henrik Biverstål Nicolas GBazan Shuai Tan Nailin Li Makiko Ohshima Marianne Schultzberg Xiaofei Li 

机构地区：[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

出　　处：《Neural Regeneration Research》2025年第3期873-886,共14页中国神经再生研究（英文版）

基　　金：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?hlén Foundation,No.233055(to MS);The Swedish Fund for Research without Animal Experiments(to MS);the Swedish Dementia Foundation(to MS);the Brain foundation,No.FO2022-0131(to MS)。

摘　　要：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.

关 键 词：Alzheimer's disease amyloid-β maresin MICROGLIA MONOCYTE NEUROINFLAMMATION resolution RNA-sequencing specialized pro-resolving lipid mediator 

分 类 号：R749.16[医药卫生—神经病学与精神病学]