Microglia renewal in old mice enhances the cellular fitness to cope with stroke

Microglial cells of the aged brain manifest signs of dysfunction that could contribute to the worst neurological outcome of stroke in the elderly. Treatment with colony-stimulating factor 1 receptor antagonists enables microglia depletion that is followed by microglia repopulation after interruption of the treatment, without any known harm to the mice. We used this strategy aiming to rejuvenate microglia function and ameliorate stroke outcome in aged mice. Cerebral ischemia/reperfusion induced strong innate immune responses in microglia highlighted by prominent type-I interferon signalling, together with cellular metabolic perturbances and lipid droplet biogenesis. Old age increased innate immune responses in microglia, which also showed more lipid droplets than microglia of young mice. Microglia renewal in old mice prevented the exaggerated type I interferon response observed in microglia after stroke, reduced the lipid droplet content, and improved the neurological outcome of stroke. This study shows that microglia renewal in old mice rejuvenates some features of old microglia and improves stroke outcome. Overall design: Transcriptomic analysis from Brain microglia in young (Y) (n=7) and old (O) (n=5). Induction for microglia repopulation were done in young (Y-re) (n=3) and old mices (n=8).