Thus, considering the in vitro and in vivo data described above, and given that the increase in perivascular GFAP, the augmentation of vascular CLN-5, and the structural alteration of the vessels were found to be closely related to each other, our results suggest that astrocytes mediate endothelial instability in human AD, and this is likely to be driven by secreted factors and particles such as EVs. Here, CLN5 is linked to Alzheimer disease.