Distinct immune signatures associated with sex and genotype in the 12m novel hAPP hAPOE mouse risk model of Alzheimer’s disease

Abstract

AbstractBackgroundUnderstanding the biology of model systems is critically important in the identification of biomarkers to delay or prevent Alzheimer’s disease. Previous findings in our group demonstrate sex differences in immune transcripts in the AD brain and in the humanized apolipoprotein E (APOE) mouse risk model. With this study, we extend these discoveries to further investigate the effect of APOE genotype using a novel risk mouse model with humanized amyloid precursor protein (APP) and humanized‐APOE transgenes (Jackson Laboratory). We test the hypothesis that during midlife aging, hAPP hAPOE ε4/4 genotype, and female sex will show increased risk profiles for Aβ 42:40 ratio and immunophenotypes associated with Alzheimer’s disease.MethodTo identify midlife (12 months; human correlate 44 years) immunophenotypes that may contribute to AD 3 different risk genotypes were studied: hAPP (6 male /6 female), hAPP hAPOE ε3/3 (16 male/16 female), and hAPP hAPOE ε4/4 (16 male /16 female). The left hemisphere of the brain was collected and prepared for multi‐color flow cytometry. Microglial reactivity (MHCII, CD68), phagocytosis (pHrodo), oxidative stress (CellRox), and the presence of lymphocytes (CD3, CD4, CD8, CD19) were determined. Peripheral blood was collected and assessed for monocytes and lymphocytes while plasma was isolated and ELISA was used to detect the presence of Aβ 40‐42, and levels of pro‐inflammatory cytokines. Female animals were monitored daily by lavage to determine midlife endocrine status.ResulthAPP hAPOE ε4/4 animals demonstrated accelerated endocrine aging compared to hAPP hAPOE ε3/3 animals. Plasma beta‐amyloid 42:40 ratio, and levels of IL‐1B, and IL‐6 showed a significant interaction between sex and hAPP hAPOE genotype (p<0.05, p<0.05, p<0.05). Plasma levels of IL‐5 and CXCL1 trended toward genotype significance with p = 0.0544 and p = 0.0556, respectively. Percentage of MHCII+ activated microglia was significantly impacted by sex (p = 0.0005) and by genotype (p<0.0001).ConclusionThe interaction between hAPP and hAPOE genotype, in coordination with biological sex significantly impacts immunophenotypes of the CNS and periphery during midlife aging. Precision interventions targeting sex and genotype‐dependent prodromal immune biomarkers may serve as an opportunity to support homeostatic immune milieu or to modulate harmful inflammatory signaling and reduce risk of AD or delay AD onset.