Mouse and human microglial phenotypes in Alzheimer’s disease are controlled by amyloid plaque phagocytosis through Hif1α

The important role of microglia, the brain’s resident immune cells, in Alzheimer’s disease (AD) is now well recognized, however their molecular and functional diversity and underlying mechanisms still remain controversial. To transcriptionally and functionally characterize the diversity of microglia in AD and aging, we isolated the amyloid plaque-containing (XO4+) and non-containing (XO4−) microglia from an AD mouse model. Transcriptomics analysis unveiled independent transcriptional trajectories in ageing and AD. XO4+ microglial transcriptomes linked plaque phagocytosis to altered expression of bona fide late onset AD genetic risk factors. We further revealed that the XO4+ transcriptional program is present in a subset of human microglia from AD patients and is a direct and reversible consequence of Aβ plaque phagocytosis. Conversely, XO4− microglia in AD displayed an accelerated ageing signature and contained more intracellular post synaptic material than plaque-containing microglia, despite reduced active synaptosome phagocytosis. Mechanistically, we predicted HIF1α as a core regulator of the XO4−/XO4+ axis, and further validated the mechanism in vitro using human stem cell-derived microglia like cells and primary human microglia. Together these findings unveiled the molecular mechanism underpinning the functional diversity of microglia in AD, providing opportunities to develop treatments targeted at subset specific manipulation of the microglial niche.

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