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Discovery Science
In Alzheimer’s disease, the blood-brain barrier — the network of blood vessels and tissues that nourish and protect the brain from harmful substances circulating in the blood — is disrupted. Now, Mayo Clinic researchers and collaborators have discovered a unique molecular signature of blood-brain barrier dysfunction that could lead to new ways to diagnose and treat the disease. Their findings are published in Nature Communications.
“These signatures have the potential to become new biomarkers for brain changes in Alzheimer’s disease,” said senior author Nilüfer Ertekin Tanner, M.D., Ph.D., chief of the Department of Neuroscience at Mayo Clinic and leader of the Alzheimer’s Disease Genetics and Endophenotype Laboratory on the Mayo Clinic campus in Florida.
To conduct their study, the research team analyzed human brain tissue from the Mayo Clinic Brain Bank, as well as public datasets and brain tissue samples from collaborating institutions. The study cohort included brain tissue samples from 12 patients with Alzheimer’s disease and 12 healthy patients who had not been diagnosed with Alzheimer’s disease. All participants had donated their tissue for scientific research. Using these datasets and external datasets, the team analyzed thousands of cells in more than six brain regions. According to the researchers, this is one of the most rigorous studies to date of the blood-brain barrier in Alzheimer’s disease.
The researchers looked at brain vascular cells, which make up a small proportion of cell types in the brain, to investigate the 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, astrocytes, to see if and how they interact.
The researchers found that in samples from Alzheimer’s patients, communication between these cells was altered through two molecules called VEGFA, which stimulates blood vessel growth, and SMAD3, which plays a key role in cellular responses to the external environment. Using cell and zebrafish models, the researchers validated their finding that elevated levels of VEGFA in the brain lead to decreased levels of SMAD3.
The research team used stem cells taken from blood and skin samples from Alzheimer’s donors and control subjects. They treated the cells with VEGFA and looked at how that affected SMAD3 levels and overall vascular health. VEGFA treatment reduced SMAD3 levels in brain pericytes, indicating an interaction between these molecules.
Donors with higher blood SMAD3 levels had less vascular damage and better Alzheimer’s-related outcomes, the researchers said. The team said further studies are needed to determine how SMAD3 levels in the brain affect blood SMAD3 levels.
“Our study systematically combines a model system with valuable human brain and blood data, and this approach can potentially be used as a roadmap for future studies to prioritize molecular targets for novel therapeutics,” said Ozkan Is, PhD, co-first author of the study along with Xue Wang, PhD.
The researchers plan to further study the SMAD3 molecule and its effects on vascular and neurodegeneration in Alzheimer’s disease, and also explore other molecules that may be involved in maintaining the blood-brain barrier.
“This informative and productive research will help us better understand the specific mechanisms that influence blood-brain barrier breakdown and other vascular changes in patients with Alzheimer’s disease,” said Heather M. Snyder, PhD, vice president for medical and scientific affairs at the Alzheimer’s Association. “Understanding the biology that influences and impacts disease progression is essential to finding new avenues for new treatments and tools to detect the earliest stages of the disease.”
The research is part of a federal grant supporting a project to identify targets for Alzheimer’s disease treatment. The research was supported by the National Institutes of Health, the National Institute on Aging, an Alzheimer’s Association Zenith Fellow Award and the Mayo Clinic Center for Regenerative Biotherapeutics. For a full list of authors, funding, and disclosures, please see the paper.