Aged-related morphological and molecular changes in gliovascular units in the murine hippocampus

Astrocytes extend highly specialized perivascular endfeet that enwrap approximately 99% of the cerebrovascular surface. This interaction is crucial for maintaining the integrity of the blood-brain barrier and the homeostatic functions of astrocytes. Although disruptions of this unit are referred in various age-related neurodegenerative diseases, little is known about their role in the physiological aging. Here, we investigated morphological and molecular changes in the interactions between astrocytes and brain endothelial cells during murine aging. To do that, we used hippocampal tissue from young (2–3 months) and aged (18-24 months) C57BL/6 mice and an in vitro model of astrocyte senescence (30-35 DIV long-term cultures x 7-10 DIV control cultures). We found an aberrant perivascular coverage by astrocyte endfeet in the aged hippocampus. Supporting this finding, we observed a reduction in laminin distribution within the aged hippocampal vasculature and a decrease in the expression of genes associated with the dystrophin-glycan complex, which anchors the astrocytic cytoskeleton to the blood vessels extracellular matrix, agrin, laminin α2, and dystrophin in the aged hippocampus. Reduction in laminin α2 and dystrophin expression was also observed in cultured senescent astrocytes. Furthermore, using a single-cell RNA database previously described (Ximerakis et al. Nature Neuroscience, 2019), we identified significative changes in gene expression of molecules involved in astrocytes-brain endothelial cells interactions during aging. Our findings suggest that aging is associated with morphological and molecular alterations of gliovascular units. 

Support: CNPq, CAPES, FAPERJ, Ministério da Saúde, Instituto Nacional de Neurociência Translacional.