Core Activation Program and Selective Regional Responsiveness of Microglia in Aging and Parabiosis

Abstract Aging is associated with immune dysregulation in brain and is the biggest risk factor for many neurodegenerative diseases whereas rejuvenation interventions can mediate beneficial effects. Microglia are considered as a major player in the development of neurodegenerative disease yet, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single cell level. We identified and benchmarked several reproducible microglial states and a core set of genes leading to microglia activation in the mice brain. We investigated microglial heterogeneity and studied the impact of aging and parabiosis-mediated exposure of young and old blood on microglia subpopulations across four different brain regions including cerebellum, cortex, hippocampus, and striatum. We revealed region-specific differences in microglia subpopulation composition and age-related changes, with cerebellum and striatum displaying the most distinctive profiles and dynamic shifts compared to other brain regions. We consistently observed cerebellum as the most responsive, while striatum appeared distinctive by its minimal responsiveness to these interventions. Our findings highlighted the role of microglia in brain regional vulnerability and provided a foundation for microglia-targeted treatment for modulating brain aging. Highlights Defined the composition of different microglial populations reproducible in aging and parabiosis, benchmarking a reference for the field. Uncovered an under-appreciated core activation gene signature of microglia shared in all reactive states and regions during normal aging and old blood-induced aging. Identified region-specific gene expression changes and associated biological processes in microglia during aging and parabiosis Discovered microglial regional selectivity in response to aging and parabiosis, showing cerebellum as the most sensitive region and the striatum as the least affected. Competing Interest Statement The authors have declared no competing interest.