Microglia protect against age-associated brain pathologies

Microglia are brain-resident macrophages that contribute to central nervous system development, maturation, and preservation. Here, we examine the consequences of lifelong absence of microglia on ageing using the Csf1rFIRE/FIRE mouse model. In juvenile Csf1rFIRE/FIRE mice, we show that microglia are largely dispensable for the transcriptomic maturation of other brain cell types. In contrast, with advancing age, multiple pathologies accumulate in Csf1rFIRE/FIRE brains, astrocytes and oligodendrocyte-lineage cells become increasingly dysregulated, and white matter integrity declines, mimicking many of the pathological features of human CSF1R-related leukoencephalopathy. The thalamus is particularly sensitive to neuropathological changes in the absence of microglia, with atrophy, neuron loss, vascular disturbances, macroglial dysregulation, and severe calcifications all detected in this region. Thalamic calcification formation, which often occurs with normal ageing, is dramatically accelerated in Csf1rFIRE/FIRE brains but can be prevented via transplantation of wild-type microglia. Our results indicate that lifelong absence of microglia results in an age-related neurodegenerative condition that can be prevented by the transplantation of healthy microglia. FIRE/ (KO), FIRE/+(HET) and Fire+/+(WT) mice were processed for single cell RNA sequencing with 10X. For 6-7-week-old young samples, hippocampi from both hemispheres and the remainder of the left hemisphere were dissected (after removal of olfactory bulbs and cerebellum). for the 11-12-month-old adult samples, the left hemisphere was processed (after removal of olfactory bulbs and cerebellum); for the 16-18-month-old old samples, the whole brain was processed (after removal of olfactory bulbs and cerebellum); for the 17-19-month-old thalamus samples, thalami were dissected from both hemispheres and processed.