在晚发性阿尔茨海默病患者的个性化单核细胞衍生巨噬细胞测定中,自体血清对TREM2和APOE的影响。

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Neriman Eren, Susanna Gerike, Berk Üsekes, Oliver Peters, Nicoleta-Carmen Cosma, Julian Hellmann-Regen
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引用次数: 0

摘要

背景:与年龄相关的免疫系统恶化导致了一种被称为“炎症”的慢性低度炎症状态,并与迟发性阿尔茨海默病(LOAD)的发病机制有关。与衰老相关的循环因子引起的组织环境变化是否会改变先天免疫反应尚不清楚。与小胶质细胞一起浸润大脑的单核细胞衍生的巨噬细胞(Mo-MФs)被认为在LOAD中发挥调节作用,并且两者都表达在髓细胞2上表达的触发受体(TREM2)。载脂蛋白E(APOE)作为TREM2的配体,它们在淀粉样蛋白β(aβ)清除中的作用突出了它们在LOAD中的重要性。然而,患者自身环境(自体血清)对浸润巨噬细胞中TREM2和APOE合成的影响仍然未知。目的:为了从功能上评估患者特异性TREM2和APOE合成,我们使用LOAD患者和匹配对照(CO)的单核细胞设计了一种基于Mo-MФs的个性化测定。我们通过检查在供体自体血清(AS)存在下细胞短期(1天)和长期(10天)分化为M1、M2或M0巨噬细胞的影响,评估了每个参与者自身环境的影响。此外,还评估了短期和长期分化的Mo-MФs的性别差异和Aβ摄取能力。结果:我们发现LOAD和CO来源的细胞中TREM2和APOE蛋白水平随时间增加。虽然与标准胎牛血清(FCS)相比,AS对TREM2的调节没有差异,但AS降低了M2巨噬细胞中的APOE水平,但增加了M1巨噬细胞中的水平。有趣的是,女性LOAD患者TREM2水平较高,APOE水平较低。最后,我们报道了长期分化的CO和LOAD衍生细胞中Aβ摄取的减少,特别是在APOEε4(+)载体中。结论:我们首次证明了基于个性化Mo-MФ细胞培养的测定法适用于在患者自身的老年环境中研究功能性TREM2和APOE合成。因此,我们的策略可能为未来个性化医学的诊断和治疗方面的研究提供有用的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer's patients.

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer's patients.

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer's patients.

Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer's patients.

Background: Age-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as "inflammaging" and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown.

Objectives: To functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant's own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed.

Results: We showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers.

Conclusions: We demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.

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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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