Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease
Marie‐Victoire Guillot‐Sestier, Ana Rubio Araiz, Virginia Mela, Aline Sayd Gaban, Eoin O′Neill, Lisha Joshi, Edward T. Chouchani, Evanna L. Mills, Marina A. Lynch
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.