2024-03-15 14:30:39
Some defects in the blood vessel network of the central nervous system have been associated with early symptoms of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). This complex vascular network is what provides the necessary nutrients—especially glucose and oxygen—to activate all neuronal functions. Now, a study led by the University of Barcelona (UB) and the Bellvitge Biomedical Research Institute (IDIBELL) in Hospitalet de Llobregat reveals that the TDP-43 protein is essential to form a stable and mature network of blood vessels in the system. central nervous
According to the work, the TDP-43 protein is also decisive in maintaining the integrity of the blood-brain barrier, which prevents the arrival of toxic agents and pathogens to the central nervous system.
The project is directed by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and has the participation of teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB ), the Josep Carreras Leukemia Research Institute, and the National Center for Genomic Analysis (CNAG-CRG). The first author is Víctor Arribas, from the University of Barcelona and IDIBELL.
What is the role of the TDP-43 protein in the vascular system?
The TDP-43 protein is a key factor for the functioning of the nervous system and neuronal plasticity. It is a binding protein in DNA and RNA that regulates gene expression and its dysfunction has been associated with various neurodegenerative disorders.
Although in recent years much progress has been made in understanding the functions of TDP-43 in neurons, its role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function.
“The work reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier,” details Professor Montañez, from the Department of Physiological Sciences of the UB.
The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signaling pathways. For example, the signaling pathway through integrins that regulates the interaction of cells with the extracellular matrix and the signaling carried out by the transcription factor beta-catenin.
“In the study, we have discovered that deficiency of the TDP-43 protein alters the extracellular matrix that surrounds blood vessels and reduces beta-catenin signaling in endothelial cells,” says the researcher. “Thus, mice without endothelial TDP-43 protein present multiple hemorrhages and vascular degeneration in the brain and spinal cord.”
From left to right, researchers Pilar Villacampa, Víctor Arribas and Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, members of the research team. (Photo: University of Barcelona. CC BY)
Vascular defects and inflammatory response in neurosciences
The study authors also identify endothelial cell TDP-43 as a potential contributing factor to vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases.
«Some alterations in the blood vessels of the central nervous system – defects in the integrity of the blood-brain barrier or degeneration of endothelial cells – are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration is underlying the origin or progression of various neurological disorders – stroke, diabetic retinopathy – and some neurodegenerative diseases such as Alzheimer’s disease, ALS or LATE (in English, Limbic-predominant age-related TDP-43 encephalopathy).
The new study will help to better understand the molecular mechanisms that link vascular defects and neuroinflammation. «Now, our objective is to analyze whether defects in the function of the TDP-43 protein in the endothelium of mature vessels could be involved in ALS or in other pathologies associated with TDP-43 due to increased vascular permeability or well of the inflammation processes,” concludes Montañez.
The study is titled “Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation.” And it has been published in the academic journal JCI Insight, where it has also been highlighted on the cover as research of maximum interest. (Source: University of Barcelona)
#integrity #bloodbrain #barrier #neurodegenerative #diseases