Sex Differences in Microglial Senescence in the Context of Alzheimer's Disease

Why are two-thirds of Alzheimer's patients women? Women live longer than men, making up an ever larger share of the surviving cohort at any given age, and Alzheimer's is an age-related disease. This doesn't explain the whole of the difference, however. A dominant hypothesis is that the immune system is sufficiently different between the sexes to produce marginally greater dysfunction and neuroinflammation in women, in the same way that still incompletely understood biochemical differences lead to a greater incidence of autoimmunity in women. Researchers here produce supporting evidence for this hypothesis, showing that female Alzheimer's model mice exhibit a greater burden of cellular senescence in microglia, producing a greater level of neuroinflammation.

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 associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia.

Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old) and old (22-25 monoth-old) ages. 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 emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses 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.

This data suggests 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 determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Link: https://doi.org/10.1186/s12974-023-02870-2

Comments

Microchimerism is the reason.

Posted by: NC at September 5th, 2023 11:37 AM
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