Research Paper Volume 12, Issue 18 pp 18343—18362

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

HaoChen Liu1, , Hong Zhang1, , Yixuan Zhang1, , Sheng Xu1, , Huimin Zhao1, , Hua He1, , XiaoQuan Liu1, ,

  • 1 Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China

Received: December 4, 2019       Accepted: July 6, 2020       Published: September 28, 2020
How to Cite

Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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 1–42 for 12h and then withdraw 1–42 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 1–42 after 12h 1–42 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.


AD: Alzheimer disease; Aβ: beta-amyloid peptide; FBS: fetal bovine serum; hCMEC/D3: human cortical microvascular endothelial cell line D3; mtDNA: mitochondria DNA; MMP: mitochondrial membrane potential; AKG: α-oxoglutarate; DNMT: DNA methyltransferase; TET: ten-eleven-translocation (TET) enzymes.