New scientific clue could unlock key cellular pathway leading to neurodegenerative diseases

In Nature NeuroscienceUConn School of Medicine researchers have unveiled a new scientific designation that could unlock the most important cellular route that leads to devastating neurodegenerative diseases such as Alzheimer’s disease, and the progressive damage to the frontal and temporal lobes of the brain in frontotemporal degeneration SCLEER member (ALS).

The study, “Endotheliale TDP-43 deportation disrupts core blood-restraining opportunities in neurodegeneration”, was published on March 14, 2025. The main author, Omar Moustafa Fathy, an MD/Ph.D. Candidate at the Center for Vascular Biology at the UConn School of Medicine, conducted the research in the Senior Author Laboratory Dr. Patrick A. Murphy, university header and newly appointed interim director of the Center for Vascular Biology. The study was conducted in collaboration with Dr. RiQiang Yan, a leading expert in Alzheimer’s disease and neurodegeneration research.

This work offers a new and significant exploration of how vascular dysfunction contributes to neurodegenerative diseases, which is an example of the powerful cooperation between the Center for Vascular Biology and the Department of Neuroscience. Although clinical evidence has long suggested that dysfunction of blood-brain barrier (BBB) ​​plays a role in neurodegeneration, the specific contribution of endothelial cells remained unclear. The BBB serves as a critical protective barrier and protects the brain against circulating factors that can cause inflammation and dysfunction. Although multiple cell types contribute to their function, endothelial cells-the inside of the blood vessels are the most important component.

In the field it is often said that ‘we are only as old as our arteries’. We learn the importance of the endothelium about diseases. I have no doubt that the same would be true in neurodegeneration, but seeing what these cells did was a critical first step. “

Dr. Patrick A. Murphy, assistant professor and newly appointed interim director of the Center for Vascular Biology

Omar, Murphy and their team have taken on an important challenge: endothelial cells are rare and difficult to insulate tissues, making it even more difficult to analyze the molecular paths involved in neurodegeneration.

To overcome this, they developed an innovative approach to enrich these cells from frozen tissues stored in a large biobank sponsored by NIH. She then applied Incite SEQ, an advanced method that makes direct measurement of signal reactions at protein level possible in some cells that mark his very first use in human tissues.

This breakthrough led to a striking discovery: endothelial cells of three different neurodegenerative diseases Alzheimer’s disease (AD), Amyotrophe Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) -SHARED Fundamental similarities that distinguish them from the endothelael. An important finding was the exhaustion of TDP-43, an RNA-binding protein genetically linked to ALS-FTD and often disturbed in AD. Until now, research has mainly focused on neurons, but this study emphasizes a previously non -recognized dysfunction in endothelial cells.

“It is easy to consider blood vessels as passive pipelines, but our findings close that opinion,” says Omar. “We see strikingly similar vascular changes on several neurodegenerative diseases, which suggests that the vasculature is not only collateral damage is actively designing disease progression. Recognizing these similarities opens the door to new therapeutic possibilities that focus on the vascular system itself.”

The research team believes that this newly identified subset of endothelial cells can offer a step -by -step plan for focusing on this endothelial dysfunction to prevent the disease, and also to develop new biomarkers from the blood of patients with diseases.