Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Abstract

Background Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment that is associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old mouse hippocampus. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome, respectively, for RNA-sequencing and differential expression analyses. Flow cytometry was used to confirm the transcriptomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerge with aging. These sex DEGs identified at old age were primarily female-biased and were enriched in senescent and disease-associated microglial signatures. Pathway analysis identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology, and explore how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Association of soluble TREM2 with Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis

“…Gender-specific responses to TREM2 in inducing disease-associated microglial states were demonstrated in earlier research (Krasemann et al, 2017). A research team found that TREM2 expression levels were higher in female aged mice compared to male mice during pathway enrichment analysis of gender-specific gene expression (Ocañas et al, 2023). Genetic polymorphisms, such as the R47H mutation, may also influence gender differences, increasing AD risks predominantly in female mice (Sayed et al, 2021).…”