Vascular dementia is the second cause of dementia after Alzheimer’s, since it is responsible for around 10-20% of cases, according to the Spanish Society of Geriatrics and Gerontology. One of the reasons why it appears is the disease of small cerebral blood vessels, which restricts the supply of blood and oxygen to the brain, and is related to cognitive decline associated with aging and ischemic strokes.
A group of scientists from the University of Cambridge have developed models similar to small blood vessels in the laboratory with which they have carried out tests to demonstrate how damage to the structure that supports these vessels can cause leaks that lead to pathologies such as vascular dementia and cerebrovascular accidents. Their study has been published in Stem Cell Reports and has also identified a therapeutic target to plug these leaks and prevent small blood vessel disease in the brain.
The main risk factors for developing small blood vessel disease in the brain are hypertension and type 2 diabetes, which usually affect middle-aged people, but there are rare, inherited forms of the disease that can manifest in younger people, around thirty-something years old. In both cases, the characteristics are similar.
Dr. Alessandra Granata, from the Department of Clinical Neurosciences at Cambridge, who led the study, explained that “despite the number of people affected worldwide by small vessel disease, we have few treatments because we do not fully understand What damages blood vessels and causes disease. “Most of what we know about the underlying causes tends to come from animal studies, but what they can tell us is limited.” Therefore, “we turned to stem cells to generate cells from the blood vessels of the brain and create a disease model ‘in a dish’ that mimics what we see in patients.”
Reverse blood vessel damage and stop blood leaks
Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at the University of Cambridge used cells taken from skin biopsies of patients with one of these rare forms of small blood vessel disease caused by a mutation in a gene called COL4.
By reprogramming skin cells they were able to create induced pluripotent stem cells, which have the ability to become almost any type of cell within the body. The team then used these stem cells to generate brain blood vessel cells and create a model of the disease that mimics defects seen in patients’ brain vessels.
The study has identified a therapeutic target to “plug” blood leaks and prevent disease of the small blood vessels in the brain
Our blood vessels are built around a structure known as the extracellular matrix, which is shaped like a network that lines and supports the small blood vessels in the brain. The COL4 gene is important for the health of this matrix, the researchers explained.
In their disease model, they discovered that the extracellular matrix is altered, particularly in the so-called “tight junctions,” which compress the cells. This causes the small blood vessels to leak, a key feature seen in small vessel disease, where blood leaks from the vessels into the brain.
The researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Normally, MMPs help maintain the extracellular matrix, but if too many are produced they can damage the structure. When they treated the blood vessels with drugs that inhibit MMPs (an antibiotic and an anticancer), they found that they reversed the damage and stopped the leak.
“These particular medications have potentially significant side effects, so they would not be viable on their own to treat small vessel disease. But they show that, in theory, targeting MMPs could stop the disease. Our model could be extended relatively easily to test the feasibility of future potential drugs,” concludes Dr. Granata.
