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

Abstract

In Alzheimers disease (AD), secretion and deposition of amyloid beta peptides (A{beta}) have been associated with blood-brain barrier dysfunction. However, the role of A{beta} 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} can trigger rapid inflammatory and thrombogenic responses within cerebral microvessels, which may exacerbate AD pathology.