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Published on: August 15, 2020
Aβ-Induced Damage Memory in hCMEC/D3 Cells Mediated by Sirtuin-1
Haochen Liu1, Yixuan Zhang1, Hong Zhang1
1Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
It is well accepted by the scientific community that the accumulation of beta-amyloid (Aβ) may be involved in endothelial dysfunction during Alzheimer's disease (AD) progression; however, anti-Aβ anti-bodies, which remove Aβ plaques, do not improve cerebrovascular function in AD animal models. The reasons for these paradoxical results require investigation. We hypothesized that Aβ exposure may cause persistent damage to cerebral endothelial cells even after Aβ is removed (referred to as cerebrovascular endothelial damage memory). In this study, we aimed to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. hCMEC/D3 cells were treated with Aβ1-42 for 12 h and then Aβ1-42 was withdrawn for another 12 h incubation to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. A mechanism-based kinetics progression model was developed to investigate the dynamic characters of the cerebrovascular endothelial damage. After Aβ1-42 was removed, the sirt-1 levels returned to normal but the cell vitality did not improve, which suggests that cerebrovascular endothelial damage memory may exist in endothelial cells. Sirt-1 activator SRT2104 and NAD+ (Nicotinamide Adenine Dinucleotide) supplement may dose-dependently relieve the cerebrovascular endothelial damage memory. sirt-1 inhibitor EX527 may exacerbate the cerebrovascular endothelial damage memory. Kinetics analysis suggested that sirt-1 is involved in initiating the cerebrovascular endothelial damage memory; otherwise, NAD+ exhaustion plays a vital role in maintaining the cerebrovascular endothelial damage memory. This study provides a novel feature of cerebrovascular endothelial damage induced by Aβ.
Insights
Alzheimer's disease (AD) research reveals beta-amyloid (Aβ) may cause lasting brain endothelial cell damage, termed "memory." This damage persists even after Aβ removal, impacting cerebrovascular function in AD.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Beta-amyloid (Aβ) accumulation is linked to endothelial dysfunction in Alzheimer's disease (AD).
- Current anti-Aβ therapies show limited efficacy in improving cerebrovascular function in AD models.
- The persistence of Aβ-induced endothelial damage, even after Aβ clearance, is not well understood.
Purpose of the Study:
- To investigate the existence of cerebrovascular endothelial damage memory in human cerebral microvascular endothelial cells (hCMEC/D3).
- To explore the role of sirt-1 and Nicotinamide Adenine Dinucleotide (NAD+) in Aβ-induced endothelial damage memory.
- To develop a kinetics model for understanding the dynamics of Aβ-induced cerebrovascular endothelial damage.
Main Methods:
- hCMEC/D3 cells were exposed to Aβ1-42 for 12 hours, followed by a 12-hour Aβ-free incubation period.
- Cell vitality and sirt-1 levels were assessed post-Aβ exposure.
- The effects of sirt-1 activator (SRT2104), sirt-1 inhibitor (EX527), and NAD+ supplementation were evaluated.
- A mechanism-based kinetics progression model was employed to analyze damage dynamics.
Main Results:
- Endothelial cells exhibited reduced vitality even after Aβ1-42 removal, suggesting cerebrovascular endothelial damage memory.
- Sirt-1 levels normalized post-Aβ removal, but cell vitality remained impaired.
- Sirt-1 activator SRT2104 and NAD+ supplementation dose-dependently ameliorated the damage memory.
- Sirt-1 inhibition exacerbated the damage memory, while NAD+ depletion was critical for its maintenance.
Conclusions:
- Cerebrovascular endothelial damage memory induced by beta-amyloid (Aβ) exists in endothelial cells.
- Sirt-1 is involved in initiating Aβ-induced endothelial damage memory.
- Nicotinamide Adenine Dinucleotide (NAD+) depletion plays a crucial role in maintaining this persistent endothelial damage, offering potential therapeutic targets for Alzheimer's disease.
