Mayo Clinic researchers have uncovered molecular signatures of blood-brain barrier dysfunction in Alzheimer’s, offering new avenues for diagnosis and treatment based on extensive tissue analysis and cellular studies.
The blood-brain barrier — a network of blood vessels and tissues that nurtures and protects the brain from harmful substances circulating in the blood — is disrupted in Alzheimer’s disease. Researchers at Mayo Clinic, along with their collaborators, have identified unique molecular signatures of this dysfunction, potentially leading to new diagnostic and therapeutic approaches for the disease. Their findings are published in Nature Communications.
“These signatures have high potential to become novel biomarkers that capture brain changes in Alzheimer’s disease,” says senior author Nilüfer Ertekin-Taner, M.D., Ph.D., chair of the Department of Neuroscience at Mayo Clinic and leader of the Genetics of Alzheimer’s Disease and Endophenotypes Laboratory at Mayo Clinic in Florida.
Extensive Study and Focus on Vascular Cells
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 cohort included brain tissue samples from 12 patients with Alzheimer’s disease and 12 healthy patients with no confirmed Alzheimer’s disease. All participants had donated their tissue for 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 portion of cell types in the brain, to examine molecular changes associated with Alzheimer’s disease. In particular, they looked at two cell types that play an important role in maintaining the blood-brain barrier: pericytes, the gatekeepers of the brain that maintain the integrity of blood vessels, and their support cells known as astrocytes, to determine if and how they interact.
They found Alzheimer’s disease patients’ samples exhibited altered communication between these cells, mediated by a pair of molecules known as VEGFA, which stimulates the growth of blood vessels, and SMAD3, which plays a key role in cellular responses to the external environment. Using cellular and zebrafish models, the researchers validated their finding that increased levels of VEGFA lead to lower levels of SMAD3 in the brain.
The team used stem cells from blood and skin samples of the Alzheimer’s disease patient donors and those in the control group. They treated the cells with VEGFA to see how it affected SMAD3 levels and overall vascular health. The VEGFA treatment caused a decline in SMAD3 levels in brain pericytes, indicating interaction between these molecules.
Implications of SMAD3 Levels
Donors with higher blood SMAD3 levels had less vascular damage and better Alzheimer’s disease-related outcomes, according to the researchers. The team says more research is needed to determine how SMAD3 levels in the brain impact SMAD3 levels in blood.
Researchers plan to further study the SMAD3 molecule and its vascular and neurodegenerative outcomes for Alzheimer’s disease and also search for other molecules with potential involvement in maintaining the blood-brain barrier.
Reference: “Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction” by Özkan Is, Xue Wang, Joseph S. Reddy, Yuhao Min, Elanur Yilmaz, Prabesh Bhattarai, Tulsi Patel, Jeremiah Bergman, Zachary Quicksall, Michael G. Heckman, Frederick Q. Tutor-New, Birsen Can Demirdogen, Launia White, Shunsuke Koga, Vincent Krause, Yasuteru Inoue, Takahisa Kanekiyo, Mehmet Ilyas Cosacak, Nastasia Nelson, Annie J. Lee, Badri Vardarajan, Richard Mayeux, Naomi Kouri, Kaancan Deniz, Troy Carnwath, Stephanie R. Oatman, Laura J. Lewis-Tuffin, Thuy Nguyen, Minerva M. Carrasquillo, Jonathan Graff-Radford, Ronald C. Petersen, Clifford R. Jr Jack, Kejal Kantarci, Melissa E. Murray, Kwangsik Nho, Andrew J. Saykin, Dennis W. Dickson, Caghan Kizil, Mariet Allen and Nilüfer Ertekin-Taner, 20 June 2024, Nature Communications.
DOI: 10.1038/s41467-024-48926-6
This research is part of a federal grant supporting projects that identify targets for Alzheimer’s disease treatment. The study was supported in part by the National Institutes of Health, National Institute on Aging, the Alzheimer’s Association Zenith Fellows Award and Mayo Clinic Center for Regenerative Biotherapeutics.
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