Systemic inflammation elicits distinct brain immune signaling dynamics in female and male mice with AD pathology.

Background: Women are disproportionately affected by Alzheimer's disease (AD), even after adjusting for age and socioeconomic status. Sex‐based biological differences in immune response, including hormonal and X‐linked immune genes, may contribute to differences in disease progression. However, we have limited understanding of the role of sex in modulating immune response and how these differences are affected by AD pathology. Here, we hypothesized that female and male mice would exhibit distinctive neural immune signaling in response to challenge with the pro‐inflammatory stimulus lipopolysaccharides (LPS), and that these differences would be exacerbated in model of AD pathology compared to wild‐type controls. Methods: Female and male six‐month‐old 5xFAD amyloid beta (Aβ) and wild type (WT) littermate mice were interperitoneally injected with LPS or saline vehicle once daily for 0,1, or 4 days (N=4). Luminex multiplexed ELISAs was used to quantify inflammatory cytokines, MAPK intracellular signaling phospho‐proteins in cortical tissues. Results: In the saline group, we observed no differences between females and males in either 5xFAD or WT mice. Additionally, in wild type mice, we observed no significant differences between females and males after either one or four daily injections of LPS. In contrast, in 5xFAD mice injected with LPS, we found significant differences between females and males after either one or four once daily injections. In particular, female 5xFAD mice after a single injection exhibited significantly increased profile (p=0.014, two tailed t‐test) of phospho‐proteins and cytokines, including MEK, cJUN, IL‐13, IL‐17, IL‐10, and IL‐1α compared to males. After four once‐daily LPS injections, female 5xFAD mice exhibited a significantly different profile (p=0.016, two tailed t‐test) consisting of increased phosphorylation of ATF2, Mek, cJUN, and HSP‐27, together with decreased expression of multiple proinflammatory cytokines including IL‐9, VEGF, MIP‐1β compared to males. Conclusions: Our data reveal that although sex is not a significant determinant of neural immune response in WT mice, it significantly affects neural immune response to LPS challenge in 5xFAD mice. These data suggest distinctive immune processes in female vs male 5xFAD mice that are not present in healthy controls. Future work will consider the effects of Aβ pathology on these results. [ABSTRACT FROM AUTHOR]