Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

An aged circulatory environment can activate microglia, reduce neural precursor cell activity, and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects including microglial reactivity and cognitive deficits in old mouse brains. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier (BBB) as a possible target to treat age-related neurodegeneration.