Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Astrocytes from Humanized Targeted Replacement Mice.

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2023-01-01 DOI:10.1177/17590914221144549
Isha Mhatre-Winters, Aseel Eid, Yoonhee Han, Kim Tieu, Jason R Richardson
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Abstract

Apolipoprotein E4 (APOE4) genotype and sex are significant risk factors for Alzheimer's disease (AD), with females demonstrating increased risk modulated by APOE genotype. APOE is predominantly expressed in astrocytes, however, there is a lack of comprehensive assessments of sex differences in astrocytes stratified by APOE genotype. Here, we examined the response of mixed-sex and sex-specific neonatal APOE3 and APOE4 primary mouse astrocytes (PMA) to a cytokine mix of IL1b, TNFa, and IFNg. Pro-inflammatory and anti-inflammatory cytokine profiles were assessed by qRT-PCR and Meso Scale Discovery multiplex assay. Mixed-sex APOE4 PMA were found to have higher basal messenger RNA expression of several pro-inflammatory cytokines including Il6, Tnfa, Il1b, Mcp1, Mip1a, and Nos2 compared to APOE3 PMA, which was accompanied by increased levels of these secreted cytokines. In sex-specific cultures, basal expression of Il1b, Il6, and Nos2 was 1.5 to 2.5 fold higher in APOE4 female PMA compared to APOE4 males, with both being higher than APOE3 PMA. Similar results were found for secreted levels of these cytokines. Together, these findings indicate that APOE4 genotype and female sex, contribute to a greater inflammatory response in primary astrocytes and these data may provide a framework for investigating the mechanisms contributing to genotype and sex differences in AD-related neuroinflammation.

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性别和APOE基因型改变人源化靶向替代小鼠原发性星形胶质细胞的基础和诱导炎症状态。
载脂蛋白E4 (APOE4)基因型和性别是阿尔茨海默病(AD)的重要危险因素,APOE基因型调节女性患病风险增加。APOE主要在星形胶质细胞中表达,然而,缺乏对APOE基因型分层星形胶质细胞性别差异的综合评估。在这里,我们研究了混合性别和性别特异性的新生儿APOE3和APOE4原代小鼠星形胶质细胞(PMA)对IL1b、TNFa和IFNg混合细胞因子的反应。通过qRT-PCR和Meso Scale Discovery多重检测评估促炎和抗炎细胞因子谱。与APOE3 PMA相比,混合性别APOE4 PMA具有更高的几种促炎细胞因子的基础信使RNA表达,包括Il6, Tnfa, Il1b, Mcp1, Mip1a和Nos2,并伴有这些分泌细胞因子的水平升高。在性别特异性培养中,与APOE4男性相比,APOE4女性PMA中Il1b, Il6和Nos2的基础表达量高出1.5至2.5倍,两者均高于APOE3 PMA。这些细胞因子的分泌水平也发现了类似的结果。总之,这些发现表明APOE4基因型和女性性别有助于原发性星形胶质细胞更大的炎症反应,这些数据可能为研究ad相关神经炎症中基因型和性别差异的机制提供框架。
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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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