Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Abstract

Senescence-associated alterations in microglia may have profound impact on cerebral homeostasis and stroke outcomes. However, the lack of a transcriptome-wide comparison between young and aged microglia in the context of ischemia limits our understanding of aging-related mechanisms. Herein, we performed RNA sequencing analysis of microglia purified from cerebral hemispheres of young adult (10-week-old) and aged (18-month-old) mice five days after distal middle cerebral artery occlusion or after sham operation. Considerable transcriptional differences were observed between young and aged microglia in healthy brains, indicating heightened chronic inflammation in aged microglia. Following stroke, the overall transcriptional activation was more robust (>13-fold in the number of genes upregulated) in young microglia than in aged microglia. Gene clusters with functional implications in immune inflammatory responses, immune cell chemotaxis, tissue remodeling, and cell-cell interactions were markedly activated in microglia of young but not aged stroke mice. Consistent with the genomic profiling predictions, post-stroke cerebral infiltration of peripheral immune cells was markedly decreased in aged mice compared to young mice. Moreover, post-ischemic aged microglia demonstrated reduced interaction with neighboring neurons and diminished polarity toward the infarct lesion. These alterations in microglial gene response and behavior may contribute to aging-driven vulnerability and poorer recovery after ischemic stroke.