Synergism of ApoE4 and systemic infectious burden is mediated by the APOE-NLRP3 axis in Alzheimer's disease.

IF 5 3区 医学 Q1 CLINICAL NEUROLOGY
Psychiatry and Clinical Neurosciences Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI:10.1111/pcn.13704
Xue-Ting Liu, Xiu Chen, Na Zhao, Fan Geng, Meng-Meng Zhu, Qing-Guo Ren
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引用次数: 0

Abstract

Background: Systemic infections are associated with the development of AD, especially in individuals carrying the APOE4 genotype. However, the detailed mechanism through which APOE4 affects microglia inflammatory response remains unclear.

Methods: We obtained human snRNA-seq data from the Synapse AD Knowledge Portal and assessed the DEGs between APOE3 and APOE4 isoforms in microglia. To verify the interaction between ApoE and infectious products, we used ApoE to stimulate in vitro and in vivo models in the presence or absence of LPS (or ATP). The NLRP3 gene knockout experiment was performed to demonstrate whether the APOE-NLRP3 axis was indispensable for microglia to regulate inflammation and mitochondrial autophagy. Results were evaluated by biochemical analyses and fluorescence imaging.

Results: Compared with APOE3, up-regulated genes in APOE4 gene carriers were involved in pro-inflammatory responses. ApoE4-stimulation significantly increased the levels of NLRP3 inflammasomes and ROS in microglia. Moreover, compared with ApoE4 alone, the co-incubation of ApoE4 with LPS (or ATP) markedly promoted pyroptosis. Both NF-κB activation and mitochondrial autophagy dysfunction were contributed by the increased level of NLRP3 inflammasomes induced by ApoE4. Furthermore, the pathological impairment induced by ApoE4 could be reversed by NLRP3 KO.

Conclusions: Our study highlights the importance of NLRP3 inflammasomes in linking ApoE4 with microglia innate immune function. These findings not only provide a molecular basis for APOE4-mediated neuroinflammatory but also reveal the potential reason for the increased risk of AD in APOE4 gene carriers after contracting infectious diseases.

在阿尔茨海默病中,APOE4 和全身感染负担的协同作用是由 APOE-NLRP3 轴介导的。
背景:全身感染与 AD 的发病有关,尤其是在携带 APOE4 基因型的个体中。然而,APOE4影响小胶质细胞炎症反应的具体机制仍不清楚:我们从Synapse AD Knowledge Portal获得了人类snRNA-seq数据,并评估了小胶质细胞中APOE3和APOE4同工酶之间的DEGs。为了验证载脂蛋白E与感染产物之间的相互作用,我们使用载脂蛋白E在有或没有LPS(或ATP)的情况下刺激体外和体内模型。我们进行了 NLRP3 基因敲除实验,以证明 APOE-NLRP3 轴是否是小胶质细胞调节炎症和线粒体自噬不可或缺的因素。结果通过生化分析和荧光成像进行了评估:结果:与 APOE3 相比,APOE4 基因携带者中上调的基因参与了促炎症反应。载脂蛋白E4刺激会显著增加小胶质细胞中NLRP3炎性体和ROS的水平。此外,与单独使用载脂蛋白E4相比,载脂蛋白E4与LPS(或ATP)共孵育能明显促进脓毒症。NF-κB 激活和线粒体自噬功能障碍都是由载脂蛋白 E4 诱导的 NLRP3 炎性体水平升高造成的。此外,NLRP3 KO可逆转载脂蛋白E4诱导的病理损伤:我们的研究强调了 NLRP3 炎性体在将载脂蛋白 E4 与小胶质细胞先天免疫功能联系起来方面的重要性。这些发现不仅为APOE4介导的神经炎症提供了分子基础,还揭示了APOE4基因携带者在感染传染病后患AD风险增加的潜在原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.40
自引率
4.20%
发文量
181
审稿时长
6-12 weeks
期刊介绍: PCN (Psychiatry and Clinical Neurosciences) Publication Frequency: Published 12 online issues a year by JSPN Content Categories: Review Articles Regular Articles Letters to the Editor Peer Review Process: All manuscripts undergo peer review by anonymous reviewers, an Editorial Board Member, and the Editor Publication Criteria: Manuscripts are accepted based on quality, originality, and significance to the readership Authors must confirm that the manuscript has not been published or submitted elsewhere and has been approved by each author
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