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The study, “TDP-43 endothelial depletion disrupts the basic hemato-encephalic barrier roads in neurodegeneration”, was published on March 14, 2025. The main author, Omar Moustafa Fathy, an MD / PH.D. The candidate of the Center for Vascular Biology of the Uconn School of Medicine Main, Dr. Patrick A. Murphy, Associate Professor and Acting Director of the Center for Vascular Biology. The study was carried out in collaboration with Dr. Riqiang Yan, a leading expert in research on the disease and neurodegeneration of Alzheimer’s.

This work provides a new and significant exploration of the way in which vascular dysfunction contributes to neurodegenerative diseases, illustrating the powerful collaboration between the Center for Vascular Biology and the Department of Neuroscience. While clinical evidence has long suggested that the dysfunction of the blood-brain barrier (BBB) ​​plays a role in neurodegeneration, the specific contribution of endothelial cells has remained clear. The BBB serves as a critical protective barrier, protecting the brain from circulating factors that could cause inflammation and dysfunction. Although several types of cells contribute to its function, endothelial cells – the inner lining of blood vessels – are its main component.

“It is often said in the field that” we are not as old as our arteries “. Through illnesses, we learn the importance of endothelium. I had no doubt that it would be true in neurodegeneration, but to see what these cells were doing was a first critical step,” explains Murphy.

Omar, Murphy and their team have taken up a key challenge: endothelial cells are rare and difficult to isolate tissues, which makes it even more difficult to analyze the molecular tracks involved in neurodegeneration.

To overcome this, they have developed an innovative approach to enrich these cells from frozen tissues stored in a large biobank sponsored by NIH. They then applied incites, a cutting -edge method which allows a direct measurement of signaling responses to protein level in unique cells – marking its first use in human tissues.

This breakthrough has led to a striking discovery: endothelial cells of three different neurodegenerative diseases – Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) – shared fundamental similarities which separated them from the endothelium in healthy agging. A key conclusion was the exhaustion of TDP-43, a binding protein with RNA genetically linked to the ALS-FD and commonly disturbed in AD. Until now, research has been focused mainly on neurons, but this study highlights previously unrecognized dysfunction in endothelial cells.

“It is easy to consider blood vessels as passive pipelines, but our results question this point of view,” explains Omar. “In several neurodegenerative diseases, we see surprisingly similar vascular changes, suggesting that the vascular system is not only collateral damage – it actively shapes the progression of the disease. The recognition of these common points opens the door to new therapeutic possibilities that target the vascular system itself.”

The research team believes that this newly identified subset of endothelial cells could provide a roadmap to target this endothelial disinction to avoid disease, as well as to develop new biomarkers from the blood of patients with disease.

The funding was provided by the start -up funds of the Uconn School of Medicine and Department of Cell Biology, of the Center for Vascular Biology and Calhoun Cardiology Center, American Heart Innovative Association Project Award 19Oploi34770151 (in PAM); The NIH National Heart, Lung and Blood Institute Grants K99 / R00-HL125727 and RF1-NS117449 (in PAM); American Heart Association Predoctoral Award 23PRE1027078 (in OMFO) R01-AG046929 and R01-NS074256 (in RY) and NIH GM135592 (in BH).

The study, “TDP-43 endothelial depletion disrupts the basic hemato-encephalic barrier roads in neurodegeneration”, was published on March 14, 2025. The main author, Omar Moustafa Fathy, an MD / PH.D. The candidate of the Center for Vascular Biology of the Uconn School of Medicine Main, Dr. Patrick A. Murphy, Associate Professor and Acting Director of the Center for Vascular Biology. The study was carried out in collaboration with Dr. Riqiang Yan, a leading expert in research on the disease and neurodegeneration of Alzheimer’s.

This work provides a new and significant exploration of the way in which vascular dysfunction contributes to neurodegenerative diseases, illustrating the powerful collaboration between the Center for Vascular Biology and the Department of Neuroscience. While clinical evidence has long suggested that the dysfunction of the blood-brain barrier (BBB) ​​plays a role in neurodegeneration, the specific contribution of endothelial cells has remained clear. The BBB serves as a critical protective barrier, protecting the brain from circulating factors that could cause inflammation and dysfunction. Although several types of cells contribute to its function, endothelial cells – the inner lining of blood vessels – are its main component.

“It is often said in the field that” we are not as old as our arteries “. Through illnesses, we learn the importance of endothelium. I had no doubt that it would be true in neurodegeneration, but to see what these cells were doing was a first critical step,” explains Murphy.

Omar, Murphy and their team have taken up a key challenge: endothelial cells are rare and difficult to isolate tissues, which makes it even more difficult to analyze the molecular tracks involved in neurodegeneration.

To overcome this, they have developed an innovative approach to enrich these cells from frozen tissues stored in a large biobank sponsored by NIH. They then applied incites, a cutting -edge method which allows a direct measurement of signaling responses to protein level in unique cells – marking its first use in human tissues.

This breakthrough has led to a striking discovery: endothelial cells of three different neurodegenerative diseases – Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) – shared fundamental similarities which separated them from the endothelium in healthy agging. A key conclusion was the exhaustion of TDP-43, a binding protein with RNA genetically linked to the ALS-FD and commonly disturbed in AD. Until now, research has been focused mainly on neurons, but this study highlights previously unrecognized dysfunction in endothelial cells.

“It is easy to consider blood vessels as passive pipelines, but our results question this point of view,” explains Omar. “In several neurodegenerative diseases, we see surprisingly similar vascular changes, suggesting that the vascular system is not only collateral damage – it actively shapes the progression of the disease. The recognition of these common points opens the door to new therapeutic possibilities that target the vascular system itself.”

The research team believes that this newly identified subset of endothelial cells could provide a roadmap to target this endothelial disinction to avoid disease, as well as to develop new biomarkers from the blood of patients with disease.

The funding was provided by the start -up funds of the Uconn School of Medicine and Department of Cell Biology, of the Center for Vascular Biology and Calhoun Cardiology Center, American Heart Innovative Association Project Award 19Oploi34770151 (in PAM); The NIH National Heart, Lung and Blood Institute Grants K99 / R00-HL125727 and RF1-NS117449 (in PAM); American Heart Association Predoctoral Award 23PRE1027078 (in OMFO) R01-AG046929 and R01-NS074256 (in RY) and NIH GM135592 (in BH).

The study, “TDP-43 endothelial depletion disrupts the basic hemato-encephalic barrier roads in neurodegeneration”, was published on March 14, 2025. The main author, Omar Moustafa Fathy, an MD / PH.D. The candidate of the Center for Vascular Biology of the Uconn School of Medicine Main, Dr. Patrick A. Murphy, Associate Professor and Acting Director of the Center for Vascular Biology. The study was carried out in collaboration with Dr. Riqiang Yan, a leading expert in research on the disease and neurodegeneration of Alzheimer’s.

This work provides a new and significant exploration of the way in which vascular dysfunction contributes to neurodegenerative diseases, illustrating the powerful collaboration between the Center for Vascular Biology and the Department of Neuroscience. While clinical evidence has long suggested that the dysfunction of the blood-brain barrier (BBB) ​​plays a role in neurodegeneration, the specific contribution of endothelial cells has remained clear. The BBB serves as a critical protective barrier, protecting the brain from circulating factors that could cause inflammation and dysfunction. Although several types of cells contribute to its function, endothelial cells – the inner lining of blood vessels – are its main component.

“It is often said in the field that” we are not as old as our arteries “. Through illnesses, we learn the importance of endothelium. I had no doubt that it would be true in neurodegeneration, but to see what these cells were doing was a first critical step,” explains Murphy.

Omar, Murphy and their team have taken up a key challenge: endothelial cells are rare and difficult to isolate tissues, which makes it even more difficult to analyze the molecular tracks involved in neurodegeneration.

To overcome this, they have developed an innovative approach to enrich these cells from frozen tissues stored in a large biobank sponsored by NIH. They then applied incites, a cutting -edge method which allows a direct measurement of signaling responses to protein level in unique cells – marking its first use in human tissues.

This breakthrough has led to a striking discovery: endothelial cells of three different neurodegenerative diseases – Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) – shared fundamental similarities which separated them from the endothelium in healthy agging. A key conclusion was the exhaustion of TDP-43, a binding protein with RNA genetically linked to the ALS-FD and commonly disturbed in AD. Until now, research has been focused mainly on neurons, but this study highlights previously unrecognized dysfunction in endothelial cells.

“It is easy to consider blood vessels as passive pipelines, but our results question this point of view,” explains Omar. “In several neurodegenerative diseases, we see surprisingly similar vascular changes, suggesting that the vascular system is not only collateral damage – it actively shapes the progression of the disease. The recognition of these common points opens the door to new therapeutic possibilities that target the vascular system itself.”

The research team believes that this newly identified subset of endothelial cells could provide a roadmap to target this endothelial disinction to avoid disease, as well as to develop new biomarkers from the blood of patients with disease.

The funding was provided by the start -up funds of the Uconn School of Medicine and Department of Cell Biology, of the Center for Vascular Biology and Calhoun Cardiology Center, American Heart Innovative Association Project Award 19Oploi34770151 (in PAM); The NIH National Heart, Lung and Blood Institute Grants K99 / R00-HL125727 and RF1-NS117449 (in PAM); American Heart Association Predoctoral Award 23PRE1027078 (in OMFO) R01-AG046929 and R01-NS074256 (in RY) and NIH GM135592 (in BH).