Abstract
Despite regionally-dependent heterogeneity, microglia subsets in healthy brain have not been identified. Utilizing autofluorescence (AF) as a discriminating parameter, we identified two novel microglia subsets in both mice and non-human primates, termed autofluorescence-positive (AF+) and autofluorescence-negative (AF-). While AF subsets maintained a consistent ratio throughout adulthood, AF within AF+ microglia linearly increased with age. Transmission electron microscopy of AF subsets revealed a selective and age-dependent increase in size and complexity of storage bodies in AF+ cells, correlating with elevated LAMP1 levels and suggesting that storage bodies accounted for AF. AF accumulation was respectively accelerated and impaired by lysosomal and autophagy disruption in Cln3- and Atg5-deficient mice, but unaltered in Trem2-/-. Aging and Cln3-deficiency correlated with oxidative stress, increased apoptosis, and cellular loss of AF+ cells. Post-depletion repopulation kinetics revealed AF- cells as precursors of AF+ microglia via gradual accumulation of storage bodies to a set proportion in the healthy brain.
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