Modeling mtDNA hypermethylation vicious circle mediating Aβ-induced endothelial damage memory in HCMEC/D3 cell.

It is well accepted that accumulation of beta-amyloid (Aβ) may involve in endothelial dysfunction during the Alzheimer's disease (AD) progression. However, cerebrovascular function cannot be improved by removing Aβ in AD animal models. The reasons for these paradoxical results still remain to be further investigated. We hypothesize that Aβ exposure may cause persistence damage to cerebral endothelial cell even after Aβ is removed (termed as cerebrovascular endothelial damage memory) mitochondria DNA (mtDNA) hypermethylation is assumed to be involved in this process. The aim of this study is to investigate whether Aβ exposure induces cerebrovascular endothelial damage memory in endothelial cells and mtDNA hypermethylation involves in this process. The hCMEC/D3 cell is 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. The levels of mtDNA methylation and cell vitality were not improved by removing Aβ1-42 after 12h Aβ1-42 incubation which suggested that the cerebrovascular endothelial damage memory may exist in endothelial cells. Kinetics model analysis suggested that mtDNA hypermethylation involves in initiating the cerebrovascular endothelial damage memory otherwise α-oxoglutarate (AKG) exhaustion plays a vital role in maintaining this process. DNA methylation inhibitor decitabine and AKG supplement may relieve the cerebrovascular endothelial damage memory dose dependently. This study provides a novel feature of cerebrovascular endothelial damage induced by Aβ.