OC 58.1 - The amyloid peptide β increases endothelial permeability in a NADPH oxidase 1-dependent manner: a link between Alzheimer’s Disease and neurovascular inflammation

Background: Alzheimer’s disease is the most common form of dementia and is associated with the accumulation of amyloid peptide β in the brain parenchyma. Vascular damage and microvascular thrombosis contribute to the neuronal degeneration and the loss of brain function typical of this disease.

Aims: In this study, we aimed to investigate the effects of amyloid peptide β on the neurovasculature and the blood-brain barrier function.

Methods: We utilised 3xTG-AD mice as a model of Alzheimer’s. A variety of techniques were utilised, ranging from brain histology studies to proteomics. The effect of amyloid peptide β on human primary endothelial cells was investigated using various immunochemistry techniques, electrical current impedance system (ECIS) experiments, and transwell cell permeability assays.

Results: Mouse brain proteomics highlighted pro-inflammatory and pro-oxidative changes concomitant with amyloid peptide β deposition in 3xTG-AD mice at age 6 and 12 months. Upon detection of the phosphorylation of the endothelial cell-cell interaction receptor VE-cadherin in the hippocampus of 3xTG-AD mice, we focused our attention on endothelial cells and utilised two types of primary endothelial cells cultured in vitro: 1) human umbilical vein endothelial cells (HUVECs) and 2) human brain microvascular endothelial cells (hBMECs). Using an electrical current impedance system (ECIS), we discovered that the treatment of human endothelial cells with amyloid peptide β causes a loss in their barrier function, which is oxidative stress-dependent and similarly to our observation in mouse brain associates with VE-cadherin phosphorylation. The activation of the superoxide anion-generating enzyme NADPH oxidase 1 is responsible for the oxidative stress that leads to the disruption of barrier function in human endothelial cells in vitro.

Conclusion(s): In summary, we have identified a novel molecular mechanism that can explain how the accumulation of amyloid peptide β in the brain parenchyma may induce the loss of neurovascular function in Alzheimer’s patients.