APOE AND IKAROS SHAPE MICROGLIAL COLONIZATION AND MATURATION IN THE POSTNATAL HIPPOCAMPUS

Microglia are the specialized phagocytes of the brain, and they play a key role in maintaining its homeostasis. They derive from yolk sac progenitors that invade the brain parenchyma at embryonic stages, and we recently identified the milestones of their developmental trajectory. Using a combination of mathematical modeling and confocal imaging in the mouse hippocampus and cerebellum, we found a critical developmental window characterized by a transition from early proliferative cells at P2 that start synchronously becoming quiescent from P4 and finally maturate morphofunctionally around P14, when they become efficient phagocytes. We identified potential epigenetic drivers of microglial maturation using ChIP-seq of the promoter mark H3K4me3. Among the genes with reduced H3K4me3 through the critical window, we found ApoE (apolipoprotein E), whose human-specific APOE4 isoform is associated with increased Alzheimer´s disease risk. We employed a humanized APOE mouse model to show that APOE4 has an impact on microglial maturation through differential proliferation and colonization dynamics. Additionally, we used a mouse model deficient in Ikaros, a demethylase inhibitor that reduces H3K4me3 marks and has also been correlated with APOE expression. We show that Ikaros KO mice have reduced microglial proliferation and density. In both models, modifying microglial proliferation and colonization result in phagocytosis alterations, highlighting that early impairments in microglial development affect their functional maturation and pointing to APOE and Ikaros as drivers of this process. These results illuminate a novel mechanism regulating microglial developmental maturation and suggest a period of vulnerability to immune stimuli before microglia reach functional competence.