Researchers identify vascular changes in the brain that are linked to Alzheimer's disease

The blood-brain barrier — a network of blood vessels and tissues that nourishes and protects the brain from harmful substances circulating in the blood — becomes disrupted in Alzheimer's disease. Now, Mayo Clinic researchers and collaborators have uncovered unique molecular signatures of blood-brain barrier dysfunction that may point to new ways to diagnose and treat the disease.

Their findings are published in Nature Communications,

“These signatures have high potential to become new biomarkers reflecting brain changes in Alzheimer's disease,” says senior author Nilufer Ertekin-Taner, M.D., Ph.D., chair of the Department of Neuroscience at Mayo Clinic and head of the Genetics of Alzheimer's Disease and Endophenotypes Laboratory at Mayo Clinic in Florida.

To conduct the study, the research team analyzed human brain tissue from the Mayo Clinic Brain Bank, as well as published datasets and brain tissue samples from collaborating institutions. The study group included brain tissue samples from 12 patients suffering from Alzheimer's disease and 12 healthy patients who did not suffer from Alzheimer's disease.

All participants had donated their tissue to science. Using these and external datasets, the team analyzed thousands of cells in more than six brain regions, making this one of the most rigorous studies of the blood-brain barrier in Alzheimer's disease to date, according to the researchers.

They focused on brain vascular cells, which make up a small fraction of the cell types in the brain, to investigate molecular changes associated with Alzheimer's disease. In particular, they looked at two types of cells that play a key role in maintaining the blood-brain barrier: pericytes, the brain's gatekeepers that maintain the integrity of blood vessels, and their supporting cells known as astrocytes, to determine if and how they interact.

They found that samples from Alzheimer's disease patients showed altered communication between these cells, mediated by a pair of molecules called VEGFA, which stimulates blood vessel growth, and SMAD3, a molecule that plays a key role in cellular responses to the external environment.

Using cellular and zebrafish models, the researchers validated their findings that increased levels of VEGFA decrease SMAD3 levels in the brain.

The team used stem cells from Alzheimer's disease patient donors and blood and skin samples from people in a control group. They treated the cells with VEGFA to see how it affected SMAD3 levels and overall vascular health. VEGFA treatment led to a decrease in SMAD3 levels in brain pericytes, indicating an interaction between these molecules.

According to the researchers, donors who had higher levels of SMAD3 in their blood had less blood vessel damage and better outcomes related to Alzheimer's disease. The team says more research is needed to find out how SMAD3 levels in the brain affect SMAD3 levels in the blood.

The researchers plan to further study the SMAD3 molecule and its vascular and neurodegenerative consequences for Alzheimer's disease, as well as explore other molecules with possible involvement in maintaining the blood-brain barrier.