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

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Beta-amyloid (Aβ) accumulation is linked to endothelial dysfunction in Alzheimer's disease (AD).
• Removing Aβ in AD models does not always restore cerebrovascular function, suggesting persistent damage.
• The mechanisms behind this persistent damage, termed cerebrovascular endothelial damage memory, are not fully understood.

Purpose of the Study:

• To investigate if Aβ exposure induces cerebrovascular endothelial damage memory in endothelial cells.
• To determine the role of mitochondrial DNA (mtDNA) hypermethylation in this memory effect.
• To explore potential therapeutic interventions targeting this damage memory.

Main Methods:

• Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to Aβ(1-42) for 12 hours, followed by a 12-hour withdrawal period.
• Cell vitality and mtDNA methylation levels were assessed after Aβ removal.
• Kinetics modeling was used to analyze the involvement of mtDNA hypermethylation and α-oxoglutarate (AKG) in damage memory.
• The effects of a DNA methylation inhibitor (decitabine) and AKG supplementation were evaluated.

Main Results:

• Endothelial cell vitality and mtDNA methylation levels did not recover after Aβ removal, indicating the presence of cerebrovascular endothelial damage memory.
• Kinetics analysis suggested mtDNA hypermethylation initiates the damage memory, while AKG exhaustion maintains it.
• Decitabine and AKG supplementation dose-dependently ameliorated the Aβ-induced cerebrovascular endothelial damage memory.

Conclusions:

• Aβ exposure induces a persistent cerebrovascular endothelial damage memory in endothelial cells.
• mtDNA hypermethylation plays a key role in initiating this damage memory.
• AKG exhaustion is crucial for maintaining the damage memory, which can be potentially reversed by decitabine and AKG supplementation.