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76 reviewsSUMMARYAtherosclerosis (AS) has been shown to be an independent risk factor for vascular cognitive impairment (VCI),but the mechanisms remain unclear. Here, we found that AS circulating exosomes exacerbated ischemicwhite matter injury and VCI. Exosomes originating from macrophage-derived foam cells targeted microglia.Mechanistically, foam cell-derived exosomes transmitted redox imbalance, mitochondrial dysfunction, andmetabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis. Anti-miR-101-3p or activation of Nrf2,both genetically and pharmacologically, could antagonize AS exosomes and ameliorate VCI. In conclusion,our findings reveal a distant connection between peripheral macrophages and brain microglia, which provides new insights and potential targets of AS-induced VCI.
