Amyloid-β aggregates induce vasculopathy via ferroptosis in brain endothelial cells

초록

Amyloid-beta (A beta) plaque is the defining pathological feature of Alzheimer's disease (AD) and a target of various therapeutic agents for affected patients. Recent studies have demonstrated the dysfunction of the blood-brain barrier (BBB) in AD; however, how A beta plaque induces BBB dysfunction, particularly in brain endothelial cells (ECs), remains elusive. This study investigates the lipid peroxidation-mediated ferroptosis pathway induced by A beta via conducting RNA sequencing, phosphorylation analysis, metabolite analysis, western blotting, and immunofluorescent staining both in vitro and in vivo. Here, we demonstrate that A beta is associated with lipid metabolic pathways following A beta exposure in brain ECs. Additionally, A beta aggregates induce the formation and accumulation of peroxidized lipid droplets. Lastly, A beta is significantly reduced in brain ECs and 5xFAD mice by the inhibition of the lipid metabolic pathway associated with lipid peroxidation and ROS formation. Our findings from in vitro and in vivo both suggest that A beta plays a causative role in the process of lipid peroxidation and might provide a potential target for the development of therapeutic interventions for AD.

키워드