A research project led by the Center for Neuroscience and Cell Biology of the University of Coimbra (CNC-UC) is studying the role of a protein called TDP-43 in Alzheimer's disease. Although it is known that this protein is deregulated in other diseases, it has been little studied in Alzheimer's disease, although there are indications that it is altered in the disease, contributing to neurodegeneration. The research may pave the way for the identification of future therapeutic targets.

"TDP-43 is an RNA-binding protein that affects many synaptic targets (the recipients of neuronal communication), and synaptic defects are a central pathway in Alzheimer's disease. In this disease, these targets can be affected, losing their ability to respond correctly, which contributes to cognitive decline," explains Ana Rita Quadros, a researcher at CNC-UC and the Center for Innovation in Biomedicine and Biotechnology (CiBB).

Ana Rita Quadros, who coordinates the research at UC, explains that “Alzheimer's disease is a disorder characterized by progressive neuronal loss and synaptic dysfunction, leading to severe cognitive decline.” “The TDP-43 protein has been identified in 20 to 50% of Alzheimer's patients and is associated with a higher probability of cognitive decline and faster brain atrophy,” she reveals.

To study the role of this protein in the disease, the SynTDP project: Decoding the contribution of TDP-43 for synaptic failure in Alzheimer's Disease will run until August 2027. It is funded with more than €207,000 (€207,183.12, to be precise) under the Marie Skłodowska-Curie Post-doctoral European Fellowships Actions, promoted by the European Commission. It is supervised by Ana Luísa Carvalho, a professor in the Department of Life Sciences at the Faculty of Science and Technology of the University of Coimbra and a researcher at CNC-UC and CiBB, who specializes in synaptic biology of diseases.

Given the hypothesis that the loss of TDP-43 function in Alzheimer's disease leads to defects in synaptic RNA targets, which in turn contribute to synaptic dysfunction and cognitive deficits, Ana Rita Quadros will study “post-mortem tissues from people with Alzheimer's, induced pluripotent stem cells (cells that can give rise to any cell in the human body), and animal models to characterize the impact of TDP-43 loss on synaptic function and composition, cross-referencing these results with the RNA changes resulting from this loss of function,” the researcher shares.

"Studying the possibility that the loss of TDP-43 protein function in people diagnosed with Alzheimer's disease leads to defects in their synaptic RNA targets — which, in turn, contribute to synaptic dysfunction and, consequently, to cognitive deficits — will be fundamental to better understanding the progression of the disease and identifying therapeutic targets for the functional restoration of neurons," emphasizes Ana Rita Quadros.

For the development of the project, Ana Rita Quadros will also have the support of Massachusetts General Hospital and Harvard Medical School.