Simulated Vascular Stiffness Promotes Alzheimer’s Disease Burden In The Lab
Alzheimer’s disease has a complex and faceted set of disease mechanisms. Although it is typically defined as a disease which affects the neurons of the brain, it has become increasingly apparent that the disease also affects the vasculature of the brain in Alzheimer’s progression.
The ‘dual hit’ hypothesis suggests that damage to the brains vasculature which separates blood blow from the brain tissue (the blood-brain barrier) actually instigates the build-up of toxic proteins and neuronal damage.
It has also been shown that vascular factors such as high blood pressure and other factors which indicate an increased stiffness of arteries are associated with protein deposits, vascular inflammation and damage.
This has been investigated in a multi-institute study, where by applying different levels of pulsatile stretch to brain endothelial cells, the research group has managed to mimic the stiffening of brain blood vessels observed in older age.
Dual Hit Hypothesis
The group found that this stiffening of the brain vasculature increased the production of a range of proteins which are responsible for the build-up of amyloid-beta plaques (the characteristic protein hallmark of Alzheimer’s disease), as well as an increase in a vascular inflammatory marker and reduced molecular function of vascular cells.
These results confound the link between vascular dysfunction and neuronal death in Alzheimer’s disease, with the increased production of amyloid beta plaque related proteins observed in this study promoting neuronal death. This supports the ‘dual hit’ hypothesis, where vascular stiffening in old age may promote the increased production of neurotoxic proteins and lead to the characteristic Alzheimer’s disease protein plaque build-up.
The group performed pulsatile stretching for 18 hours at different magnitudes of stretch between 0-15%. To achieve this they used a ShellPa bioreactor system, which is designed to apply mechanical stress to the cells, thereby replicating physical stresses occurring in the body on a cell culture plate in the lab.
The authors have cited a potential limitation of this study to be from the variability of the mechanical system. Additionally, the control cell samples used for each magnitude of stretch (5-15%) weren’t taken from the same cell split passage (number of time cells are split within the lab), potentially introducing further variability.
The authors also state that in spite of these potential variable factors, the data recorded was statistically significant, and they predict that a reduction in variability would only improve the confidence in these results.
Moving forward from this study, these results could be applied in future research, with an increased focus on modulating the vascular stiffness to reduce Alzheimer’s disease onset. In addition, repeats of this study with human cell lines that express mutations seen in late onset Alzheimer’s disease could provide useful information relating to the disease.
Skin cells extracted from Alzheimer’s patients can be reprogrammed to pluripotent stem cells (cells which can be grown into multiple different cell types) and be differentiated into brain vascular cells. This would allow for the analysis of pulsatile stretch on Alzheimer’s patient cells rather than the immortalised cells used in this study.