Multiregional blood-brain barrier phenotyping identifies the prefrontal cortex as the most vulnerable region to ageing in mice

Abstract

Age-associated vascular alterations make the brain more vulnerable to neuropathologies. Research in humans and rodents has demonstrated structural, molecular, and functional alterations of the aged brain vasculature that suggest blood-brain barrier dysfunction. However, these studies focused on particular features of the blood-brain barrier and specific brain regions. Thus, it remains unclear if and which blood-brain barrier age-associated phenotypes are conserved across brain areas. Moreover, there is very limited information about how blood-brain barrier dysfunction and cell-specific phenotypes relate to each other. In this manuscript, we use immunofluorescence, transmission electron microscopy, and permeability assays to assess how age-associated blood-brain barrier molecular, structural, and functional phenotypes correlate between the blood-brain barrier cell types at three brain regions (prefrontal cortex, hippocampus, and corpus callosum) during mouse early ageing. We discovered that at 18–20 months of age, changes to the mouse blood-brain barrier are subtle. The prefrontal cortex blood-brain barrier is the most affected by age, with alterations in brain endothelial cell protein expression, blood-brain barrier permeability, basement membrane thickness, and astrocyte endfoot size when compared with young mice. Here, we deliver a detailed multicellular characterization of region-dependent blood-brain barrier changes at early stages of ageing. Our data paves the way for future studies to investigate how region-specific blood-brain barrier dysfunction may contribute to disease-associated regional vulnerability.