Researchers at the Mayo Clinic have identified unique molecular changes in the blood-brain barrier that could help diagnose and treat Alzheimer’s disease.
Mayo Clinic researchers have discovered molecular hallmarks of blood-brain barrier dysfunction in Alzheimerwhich offers new possibilities for diagnosis and treatment based on extensive tissue analysis and cell studies.
The blood-brain barrier—a network of blood vessels and tissues that nourishes the brain and protects it from harmful substances circulating in the blood—is disrupted in Alzheimer’s disease. Researchers at the Mayo Clinic and 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 communication.
“These signatures have great potential to become novel biomarkers that capture changes in the brain in Alzheimer’s disease,” said lead author Nilüfer Ertekin-Taner, MD, PhD, chief of the Division 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 without confirmed 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, the researchers said.
They focused on brain vascular cells, which make up a small subset of the cell types in the brain, to investigate molecular changes linked to Alzheimer’s disease. In particular, they looked at two cell types that play a key role in maintaining the blood-brain barrier: pericytes, the brain’s gatekeepers that maintain blood vessel integrity, and their supporting cells, known as astrocytes, to determine whether and how they interact.
They found that samples from Alzheimer’s patients showed altered communication between these cells, mediated by a pair of molecules known as VEGFA, which stimulates blood vessel growth, 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 Alzheimer’s patient donors and controls. They treated the cells with VEGFA to see how it affected SMAD3 levels and overall vascular health. VEGFA treatment caused a decrease in SMAD3 levels in brain pericytes, suggesting an interaction between these molecules.
Implications of SMAD3 levels
Donors with higher blood SMAD3 levels had less vascular damage and better outcomes for Alzheimer’s disease, the researchers said. The team says more research is needed to determine how SMAD3 levels in the brain affect SMAD3 levels in the blood.
Researchers plan to further study the SMAD3 molecule and its vascular and neurodegenerative consequences in Alzheimer’s disease, as well as other molecules that may be involved 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, CliffordR. Jr. Jack, Kejal Kantarci, Melissa E. Murray, Kwangsik Nho, Andrew J. Saykin, Dennis W. Dickson, Caghan Kizil, Mariet Allen, and Nilüfer Ertekin-Taner, June 20, 2024, Nature communication.
DOI file: 10.1038/s41467-024-48926-6
This research is part of a federal grant that supports projects identifying targets for treating Alzheimer’s disease. The study was supported in part by the National Institutes of HealthNational Institute on Aging, the Alzheimer’s Association Zenith Fellows Award, and the Mayo Clinic Center for Regenerative Biotherapeutics.