Farmington, CT – Researchers at UConn School of Medicine have identified a critical cellular pathway that may drive neurodegenerative diseases such as Alzheimer’s, frontotemporal degeneration (FTD), and amyotrophic lateral sclerosis (ALS).
The study, published in Nature Neuroscience on March 14, 2025, reveals that blood-brain barrier dysfunction, specifically in endothelial cells, plays a direct role in disease progression.
The study, titled “Endothelial TDP-43 Depletion Disrupts Core Blood-Brain Barrier Pathways in Neurodegeneration,” was led by Omar Moustafa Fathy, an MD/Ph.D. candidate at UConn’s Center for Vascular Biology, in the lab of Dr. Patrick A. Murphy, associate professor and interim director of the Center.
The work was conducted in collaboration with Dr. Riqiang Yan, a leading expert in Alzheimer’s research.
Endothelial cells form the inner lining of blood vessels and are the principal component of the blood-brain barrier (BBB), which protects the brain from harmful substances.
While prior research linked BBB dysfunction to neurodegenerative diseases, the direct role of endothelial cells remained unclear.
“It is often said in the field that ‘we are only as old as our arteries,’” said Murphy. “Across diseases we are learning the importance of the endothelium. I had no doubt the same would be true in neurodegeneration, but seeing what these cells were doing was a critical first step.”
The team faced a major challenge—endothelial cells are rare and difficult to isolate.
To overcome this, they developed an advanced method to extract these cells from frozen human brain tissue stored in an NIH-sponsored biobank. They then used inCITE-seq, a cutting-edge technique that allows direct measurement of protein-level signaling in single cells. The study marks the first time the method has been applied to human tissues.
Their analysis revealed a striking commonality across Alzheimer’s, ALS, and FTD: the depletion of TDP-43, an RNA-binding protein genetically linked to ALS-FTD and frequently disrupted in Alzheimer’s. While past studies have focused on neurons, this research highlights a previously unrecognized dysfunction in blood vessel cells.
“It’s easy to think of blood vessels as passive pipelines, but our findings challenge that view,” said Omar. “Across multiple neurodegenerative diseases, we see strikingly similar vascular changes, suggesting that the vasculature isn’t just collateral damage—it’s actively shaping disease progression. Recognizing these commonalities opens the door to new therapeutic possibilities that target the vasculature itself.”
The team believes these findings could lead to new blood-based biomarkers for early detection and novel treatments aimed at restoring endothelial function.
Funding for the study came from the UConn School of Medicine, Calhoun Cardiology Center, the American Heart Association, and multiple NIH grants.
