Abstract
Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.
Highlights
Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females
These include genes that are linked with altered risk of AD-like Apoe, Bin[1], Trem[2] and Cd3310.Sex-related differences in genes that identify homoeostatic microglia were observed with marked downregulation of P2ry[12] and upregulation of several genes that have been shown to increase in models of disease like Ctsd, Fth[1] and Lyz[2], in cells from female APP/PS1 mice (Fig. 1c)
Similar genotype- and sex-related increases were observed on other genes characteristic of DAMs/activated response microglia (ARM) including Cst[7], Aplp[2], Cd74, and Axl, and genes that are upregulated in injury and/or neuroinflammatory diseases other than AD including Gpnmb and Plxdc[2] (*p < 0.05; *p < 0.01; ***p < 0.001 WT v APP/PS1; xp < 0.05; xxp < 0.01; xxxp < 0.001, male vs. female APP/PS1; Supplementary Fig. 1)
Summary
Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Consistent with data from transcriptomic studies, several groups have reported that microglia in models of AD adopt an activated and inflammatory phenotype Such cells shift their metabolism towards glycolysis[7] and microglia isolated from the brains of aged mice and APP/PS1 mice are characterised by an inflammatory and glycolytic signature[8,9]. We sought to investigate sex-related changes in microglia and show that the shift in microglial metabolism towards glycolysis in cells from 18 month-old APP/PS1 mice, which is accompanied by inflammatory and phenotypic changes, is more profound in cells from female, compared with male, mice One consequence of these changes is a deterioration in phagocytic function. Sex-related differences in microglial phenotype were identified in post-mortem samples from AD patients and this was associated with increased amyloid load in females, compared with males.
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