Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer’s disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68⁺ microglia (brain) and CD8⁺ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII⁺ microglia and CD11b⁺CD4⁺ T cells (brain) and (2) higher CD11b⁺CD4⁺ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.

载脂蛋白 E ε4 等位基因 (APOE4) 是晚发性阿尔茨海默病 (AD) 的主要遗传风险因素。 APOE4 小鼠模型在理解疾病发病机制方面取得了进展，但啮齿类动物饲养状况等未解释的变量可能会阻碍转化结果。食物和床上用品等非无菌方面可能是啮齿动物微生物群落变化的主要来源。肠道微生物生态的改变会导致粘膜屏障受损并增加促炎信号。本研究探讨了无菌和非无菌食物和住房对氧化还原指标和人源化APOE4敲入小鼠 (hAPOe4) 免疫状态的作用。 hAPOE4 小鼠在无菌条件下饲养直至 22 个月大，然后将一组小鼠转移到非无菌饲养环境中 2 个月。 24 个月大时，通过流式细胞术/ELISA 评估氧化还原/免疫状态。与无菌饲养的小鼠相比，在非无菌条件下饲养的 hAPOE4 雌性表现出：（1）更高的神经元和小胶质细胞氧自由基产生，（2）更低的 CD68 ⁺小胶质细胞（大脑）和 CD8 ⁺ T 细胞（外周）。相比之下，非无菌环境中的 hAPOE4 雄性表现出：(1) 更高的 MHCII ⁺小胶质细胞和 CD11b ⁺ CD4 ⁺ T 细胞（大脑）和 (2) 更高的 CD11b ⁺ CD4 ⁺ T 细胞以及脂多糖结合蛋白和炎症细胞因子的水平与无菌饲养的小鼠相比，在外围。这项研究表明，无菌与非无菌的饲养条件与大脑和外周氧化还原和免疫反应的激活有关，且具有性别依赖性。 因此，住房状况可能会导致大脑和外周的不同结果。