“Sex-divergent responses to microglial depletion suggest distinct regulatory dependencies in the aged brain”
TL;DR
Sexual dimorphic responses to microglial depletion via CSF1R inhibition via CSF1R inhibition are characterized and candidate post-transcriptional mechanisms warranting further investigation are identified.
Abstract
Microglia are essential for brain homeostasis, yet their roles in the aged brain remain poorly defined. Using microRNA (miRNA) profiling, cellular-resolution spatial transcriptomics, and bulk proteomics in 21-month-old mice, we characterize sex-dimorphic responses to microglial depletion via CSF1R inhibition (PLX5622 treatment). Microglia-enriched miRNAs, notably miR-146a-5p and miR-223-3p, were downregulated across different brain regions in both sexes. Transcriptional responses were sex dimorphic: females showed predominantly cell-type-specific downregulation, while males showed bidirectional changes including upregulation of Lzts3, Shank3, and Fgfbp1 alongside downregulation of Ang. Proteomic changes were larger in magnitude and independent from mRNA changes: males exhibited 295 differentially expressed proteins (DEPs) versus 34 in females (8.7-fold difference). Male DEPs had opposing directional shifts in synaptic vesicle proteins (upregulated) and mitochondrial ATP synthesis machinery (downregulated). These data describe sex-dimorphic molecular consequences of microglial loss in the aged brain and identify candidate post-transcriptional mechanisms warranting further investigation.
