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Amyloid beta peptides (Aβ) 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 (Aβ) have been associated with blood-brain barrier dysfunction. However, the role of Aβ in endothelial cell (EC) dysfunction remains elusive. Here we investigated AD mediated EC activation by studying the effect of A...

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Published in:Neurobiology of disease 2023-06, Vol.181, p.106125-106125, Article 106125
Main Authors: Shin, Yu Jung, Evitts, Kira M., Jin, Solhee, Howard, Caitlin, Sharp-Milgrom, Margaret, Schwarze-Taufiq, Tiara, Kinoshita, Chizuru, Young, Jessica E., Zheng, Ying
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Language:English
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Summary:In Alzheimer's disease (AD), secretion and deposition of amyloid beta peptides (Aβ) have been associated with blood-brain barrier dysfunction. However, the role of Aβ in endothelial cell (EC) dysfunction remains elusive. Here we investigated AD mediated EC activation by studying the effect of Aβ 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 Aβ levels in Swe+/+ conditioned media (CM) led to stress fiber formation and upregulation of genes associated with endothelial inflammation and immune-adhesion. Perfusion of Aβ-rich Swe+/+ CM induced acute formation of von Willebrand factor (VWF) fibers in the vessel lumen, which was attenuated by reducing Aβ levels in CM. Our findings suggest that Aβ peptides can trigger rapid inflammatory and thrombogenic responses within cerebral microvessels, which may exacerbate AD pathology. •AD neuronal secretomes cause transcriptomic upregulation of EC inflammation.•Perfusion of AD media in microvessels causes EC activation and VWF fiber formation.•Inhibiting Aβ secretion with a BACE1 inhibitor or APPKO media reduced EC activation.
ISSN:0969-9961
1095-953X
1095-953X
DOI:10.1016/j.nbd.2023.106125