Summary: Researchers have identified unique molecular signatures of blood-brain barrier dysfunction in Alzheimer’s disease. They discovered impaired communication between brain vascular cells mediated by the molecules VEGFA and SMAD3. These findings could lead to new diagnostic biomarkers and treatment options for Alzheimer’s disease.
Highlights:
- VEGFA and SMAD3 play crucial roles in blood-brain barrier integrity.
- Alzheimer’s disease samples showed disrupted cellular communication in brain vascular cells.
- Higher blood levels of SMAD3 correlate with better Alzheimer’s disease outcomes.
Source: Mayo Clinic
The blood-brain barrier – a network of blood vessels and tissues that nourishes and protects the brain from harmful substances circulating in the blood – is disrupted in Alzheimer’s disease.
Now, Mayo Clinic researchers and their collaborators have discovered unique molecular signatures of blood-brain barrier dysfunction that could pave the way for new ways to diagnose and treat the disease.
Their findings are published in Nature Communications.
“These signatures have strong potential to become novel biomarkers capturing brain changes related to Alzheimer’s disease,” says lead author Nilüfer Ertekin-Taner, MD, Ph.D., chair of the clinic’s Department of Neuroscience. Mayo and head of the Department of Alzheimer’s Disease Genetics. Mayo Clinic Disease and Endophenotype Laboratory 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 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 tissues to science. Using this and external datasets, the team analyzed thousands of cells across more than six brain regions, making it 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 the brain’s cell types, to examine the molecular changes associated with Alzheimer’s disease. In particular, they studied two types of cells that play an important role in maintaining the blood-brain barrier: pericytes, the brain’s guardians that maintain the integrity of blood vessels, and their support cells called astrocytes, to determine whether and how they interact.
The researchers found that samples from Alzheimer’s patients had impaired communication between these cells, mediated by a pair of molecules called VEGFA, which stimulates blood vessel growth, and SMAD3, which plays a key role in cellular responses to the external environment. Using cell models and zebrafish, 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 from 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. VEGFA treatment caused a decrease in SMAD3 levels in brain pericytes, indicating an interaction between these molecules.
Donors with higher SMAD3 blood levels had less vascular damage and better Alzheimer’s disease outcomes, the researchers found. The team believes that further research is needed to determine 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 in Alzheimer’s disease and also to search for other molecules potentially involved in the maintenance of the blood-brain barrier.
This research is part of a federal grant to support projects aimed at identifying targets for the treatment of Alzheimer’s disease. The study was funded in part by the National Institutes of Health, the National Institute on Aging, the Alzheimer’s Association Zenith Fellows Award and the Mayo Clinic Center for Regenerative Biotherapeutics.
About this Alzheimer’s disease research news
Author: Megan Luihn
Source: Mayo Clinic
Contact: Megan Luihn – Mayo Clinic
Picture: Image credited to Neuroscience News
Original research: Free access.
“Gliovascular transcriptional disruptions in Alzheimer’s disease reveal molecular mechanisms of blood-brain barrier dysfunction” by Nilüfer Ertekin-Taner et al. Natural communications
Abstract
Gliococcal transcriptional disruptions in Alzheimer’s disease reveal molecular mechanisms of blood-brain barrier dysfunction
To uncover the molecular changes underlying blood-brain barrier dysfunction in Alzheimer’s disease, we performed single-nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte groups as the major cell types of the gliovascular unit of the blood-brain barrier.
The majority of vascular transcriptional changes occurred in pericytes. Among the vascular molecular targets thought to interact with astrocyte ligands, SMAD3upregulated in Alzheimer’s disease pericytes, has the highest number of ligands, including VEGFAdownregulated in Alzheimer’s disease astrocytes.
We validated these results with external datasets including 4,730 pericyte nuclei and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with neuroimaging findings related to Alzheimer’s disease. We determined the inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human and zebrafish iPSC models.
Here, we detect broad transcriptome changes in Alzheimer’s disease at the gliovascular unit level, prioritizing pericytic disruptions SMAD3-astrocytic VEGFA interactions and validate them in cross-species models to provide a molecular mechanism of blood-brain barrier disintegration in Alzheimer’s disease.