Molecular Link between Dementia, Blood Vessel Changes Reveals Treatment Possibilities

Roughly half of all people over the age of 85 suffer from one (or more) forms of dementia. Dementia is defined as the loss of cognitive functions (thinking, remembering, and reasoning) and behavioral functions (language skills and the ability to focus) to the extent that a person’s daily life is affected. One of the most common forms of dementia, which also increases the risk of stroke and exacerbates symptoms of Alzheimer’s disease, is cerebral small vessel disease (SVD).

Scientists from the University of Edinburgh have come one step closer to developing a potential treatment for SVD. The research is described in a paper published in Science Translational Medicine entitled “Reversal of Endothelial Dysfunction Reduces White Matter Vulnerability in Cerebral Small Vessel Disease in Rats.”

Previous research showed, through magnetic resonance scans from patients that abnormalities in white matter occur during SVD. However, the link between the changes in the blood vessels and the brain damage remained unknown.

In the current study, the researchers sought to understand the mechanism of how changes in the small blood vessels (arterioles) in the brain associated with SVD could cause damage to brain cells. To do this, the researchers used a rat model of SVD with a loss-of-function mutation in ATPase11B that caused endothelial cell dysfunction. Interestingly, a single-nucleotide polymorphism in ATPase11B is also associated with white matter abnormalities in humans with SVD.

The endothelial cell dysfunction in the SVD rat model blocked the differentiation of oligodendrocyte precursors into myelinating cells. This impaired myelination was caused by secretion of heat shock protein 90α by the dysfunctional endothelial cells.

This finding is particularly significant because humans with early, asymptomatic SVD pathology also show endothelial cell and oligodendrogial dysfunction.

The finding that endothelial cell dysfunction is one of the causes of SVD white matter disruption revealed a potential target for a therapeutic strategy. Nathan Richardson, Ph.D., the MRC’s head of molecular and cellular medicine, commented: “This study is a great example of how innovative discovery science into regenerative mechanisms can be applied to improve our understanding of how vascular changes contribute to dementia. This research in rats opens up new possibilities for developing therapies for cerebral SVD.”

Indeed, the brain cell damage in the rats caused by the blood vessel changes was prevented by treatment with endothelial cell–stabilizing drugs, providing evidence for a potential path for the development of a therapeutic approach for dementia.

Anna Williams, Ph.D., group leader at the University of Edinburgh’s MRC Centre for Regenerative Medicine, said: “This important research helps us understand why SVD happens, providing a direct link between small blood vessels and changes in the brain that are linked to dementia. It also shows that these changes may be reversible, which paves the way for potential treatments.”