Aβ-Induced Damage Memory in hCMEC/D3 Cell Mediated by Sirtuin-1

Abstract

Background: It is well accepted that accumulation of beta-amyloid (Aβ) may involve in endothelial dysfunction during the Alzheimer’s disease (AD) progression. However, anti-Aβ antibodies, which remove Aβ plaques, do not improve cerebrovascular function in AD animal models. The reasons for these paradoxical results still remain to be further investigated. We hypothesize that Aβexposure may cause persistent damage to cerebral endothelial cell even after Aβ is removed (termed as cerebrovascular endothelial damage memory). The aim of this study is to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. Method: The hCMEC/D3 cells are treated with Aβ1-42 for 12h and then withdraw Aβ1-42 for another 12h incubation to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. A mechanism based kinetics progression model is developed to investigate the dynamic characters of the cerebrovascular endothelial damage. Results: After Aβ1-42 was removed, the level of sirt-1 recovered but the cell vitality did not improved which suggested that the cerebrovascular endothelial damage memory may exist in endothelial cells. Sirt-1 activator SRT2104 and NAD+ supplement may relieve the cerebrovascular endothelial damage memory dose dependently. sirt-1 inhibitor EX527 may exacerbate the cerebrovascular endothelial damage memory. Kinetics analysis suggested that sirt-1 involves in initiating the cerebrovascular endothelial damage memory otherwise NAD+ exhaustion plays a vital role in maintaining the cerebrovascular endothelial damage memory. Conclusions: This study provides a novel feature of cerebrovascular endothelial damage induced by Aβ.