Amyloid beta peptides (A beta) from Alzheimer's disease neuronal secretome induce endothelial activation in a human cerebral microvessel model

In Alzheimer's disease (AD), secretion and deposition of amyloid beta peptides (A ss) have been associated with blood-brain barrier dysfunction. However, the role of A ss in endothelial cell (EC) dysfunction remains elusive. Here we investigated AD mediated EC activation by studying the effect of A beta secreted from human induced pluripotent stem cell-derived cortical neurons (hiPSC-CN) harboring a familial AD mutation (Swe+/+) on human brain microvascular endothelial cells (HBMECs) in 2D and 3D perfusable microvessels. We demonstrated that increased A beta levels in Swe(+/+) conditioned media (CM) led to stress fiber formation and upregulation of genes associated with endothelial inflammation and immune-adhesion. Perfusion of A beta-rich Swe(+/+) CM induced acute formation of von Willebrand factor (VWF) fibers in the vessel lumen, which was attenuated by reducing A beta levels in CM. Our findings suggest that A beta peptides can trigger rapid inflammatory and thrombogenic responses within cerebral microvessels, which may exacerbate AD pathology.

Automated summary

In Alzheimer's disease, the dysfunction of the blood-brain barrier is associated with the secretion and deposition of amyloid beta peptides. This study investigated the activation of endothelial cells by amyloid beta secreted from human induced pluripotent stem cell-derived cortical neurons with a familial Alzheimer's disease mutation. The results showed that amyloid beta promoted stress fiber formation and upregulated genes related to endothelial inflammation and immune-adhesion, leading to the formation of von Willebrand factor fibers in the vessel lumen.