Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice

• Published in: Experimental brain research 2024-03, Vol.242 (3), p.543-557
• Main Authors: Reyes-Reyes, E. M., Brown, J., Trial, M. D., Chinnasamy, D., Wiegand, J. P., Bradford, D., Brinton, R. D., Rodgers, K. E.
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer's disease; Animal models; Animals; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; CD11b antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Enzyme-linked immunosorbent assay; Female; Flow cytometry; Housing conditions; Housing Quality; Humans; Immune status; Immune System - metabolism; Immune System - pathology; Infant; Inflammation; Lipopolysaccharide-binding protein; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Transgenic; Microflora; Microglia; Microglia - pathology; Neurodegenerative diseases; Neurology; Neurosciences; Research Article; Risk factors; Sex Characteristics; Sex differences
• ISSN: 0014-4819; 1432-1106; 1432-1106
• DOI: 10.1007/s00221-023-06763-x

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.