New clue about what leads to neurodegenerative diseases such as Alzheimer’s and ELA

The study, “Endothelial exhaustion TDP-43 interrupts the central hematocerence barrier pathways in neurodegeneration,” was published on March 14, 2025. The main author, Omar Moustafa Fathy, a MD/Ph.D. The candidate at the Vascular Biology Center of the UCONN School of Medicine, conducted the investigation in the main author Dr. Patrick A. Murphy, associate professor and newly appointed interim director of the Center for Vascular Biology. The study was carried out in collaboration with Dr. Riqiang Yan, a leading expert in Alzheimer’s disease and neurodegeneration research.

This work provides a novel and significant exploration of how vascular dysfunction contributes to neurodegenerative diseases, exemplifying the powerful collaboration between the Center for Vascular Biology and the Department of Neuroscience. While clinical evidence has long suggested that hematoencephalic barrier dysfunction (BBB) ​​plays a role in neurodegeneration, the specific contribution of endothelial cells had not remained clear. BBB serves as a critical protective barrier, protecting the brain from circulating factors that could cause inflammation and dysfunction. Although multiple types of cells contribute to their function, endothelial cells, the internal lining of blood vessels, are their main component.

“It is often said in the field that” we are as old as our arteries. “In all diseases we are learning the importance of endothelium. He had no doubt about the same in neurodegeneration, but seeing what these cells were doing was a first critical step,” says Murphy.

Omar, Murphy and his team boarded a key challenge: endothelial cells are rare and difficult to isolate from tissues, which makes it even more difficult to analyze the molecular pathways involved in neurodegeneration.

To overcome this, they developed an innovative approach to enrich these cells from frozen tissues stored in a great biobanco sponsored by NIH. Then they applied Incite-Seq, an avant-garde method that allows the direct measurement of signaling responses at the level of protein in individual cells, marking their first use in human tissues.

This advance led to a surprising discovery: endothelial cells of three different neurodegenerative diseases: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ELA) and frontotemporal dementia (FTD), the shared fundamental similarities that distinguish the endothelium in the endothelium in the healthy state. A key finding was the exhaustion of TDP-43, a protein of union united genetically with ALS-FTD and commonly interrupted in AD. Until now, research has focused mainly on neurons, but this study highlights a previously not recognized dysfunction in endothelial cells.

“It’s easy to think about blood vessels as passive pipes, but our findings challenge that opinion,” says Omar. “Through multiple neurodegenerative diseases, we see surprisingly similar vascular changes, which suggests that the vasculature is not only collateral damage, it is actively forming the progression of the disease. Recognizing these points in common opens the door to new therapeutic possibilities that are directed to the vasculature itself.”

The research team believes that this recently identified subset of endothelial cells could provide a roadmap to attack this endothelial dysfunction to avoid the disease, and also to develop new biomarkers from the blood of patients with disease.

The starting funds of the Faculty of Medicine and the Department of Cell Biology of UConn Funding were provided by the Center for Vascular Biology and Cardiology Center of Calhoun, innovative Prize of the Innovative Project of the American Association 19iploi34770151 (A PAM); NIH National Heart, Lung and Blood grants K99/R00-HL125727 and RF1-NS117449 (A PAM); Predoctoral Prize of the American Association of Heart 23PRE1027078 (A omfo) R01-AG046929 and R01-NS074256 (A RY) and NIH GM135592 (A BH).