Validating ADAM10 as a Therapeutic Target for Dementia
Alzheimer's disease affects a number of elderly people, who lose their memory and their ability to take care of themselves. This disease is associated with different types of amyloid protein in the brain, a substance that can grow deadly and kill neurons when it accumulates in formations seen with Alzheimer’s disease. Our work is intended to develop a drug able to promote a pathway in the cell that limits the formation of amyloid protein. We hope that our results will contribute to ways to help people suffering from Alzheimer's disease recover their memory.
Alzheimer's disease is the most common form of dementia, a broad medical term describing several conditions affecting cognitive function. Alzheimer's disease is emerging as the most prevalent and socially disruptive illness of aging populations since we are still lacking an adequate cure.
The disease is linked with a peptide called amyloid β that impairs communication among neurons. A-disintegrin and metalloproteinase 10 (ADAM10) is an enzyme that prevents amyloid β generation. Therefore, the main goal of my project is intended to develop a drug able to promote ADAM10 activity in the neurons, thus limiting the formation of amyloid β.
In the first portion of the project, I will develop cell-permeable peptides as drugs able to increase ADAM10 activity. These cell-permeable peptides penetrate into the cells and are able to interfere with the process responsible for ADAM10 removal from the membranes. Therefore, cell-permeable peptides are able to increase ADAM10 level at the membrane and, thereby to stimulate its activity. First, I will test different cell-permeable peptides to verify their efficacy and specificity.
In the second portion of the project, I will administer the most effective cell-permeable peptide to mice that model Alzheimer's disease. I will evaluate whether the treatment with the cell-permeable peptide influences the activity of ADAM10 and the formation of amyloid β. Moreover I will analyze whether this drug is able to modify memory loss and Alzheimer's disease pathology in these mice models.
This proposal is very innovative because I aim at targeting ADAM10, a player in Alzheimer's disease that is ranked “high” in the cascade of pathogenic events. Therefore I hope to modify the progression of the disease, thus paving the way for a disease-modifying therapy of Alzheimer's disease. Moreover, I have the chance to improve the technology of cell-permeable peptides that require additional effort to translate the results obtained at preclinical stage to the clinical framework.
The results obtained from this project potentially will support the role of ADAM10 as therapeutic target. Moreover the research field will benefit from several critical insights that may have a profound impact on developing strategies for AD therapy. My hope is that the results of this project will contribute to helping people suffering from Alzheimer's disease recover their memory.
About the Researcher
Elena Marcello is a research fellow in the laboratory of Monica Di Luca, PhD, Department of Pharmacological and Biomolecular Sciences, University of Milano, Italy. She completed her doctoral studies in pharmacotoxicological and pharmacognostic sciences and pharmaceutical biotechnology in 2006, at the University of Milano. She directed her attention to discoveringa molecular link between primary and secondary pathogenic events in Alzheimer’s disease, focusing on the amyloid cascade and synaptic dysfunction. In order to study new mechanisms responsible for ADAM10 trafficking, in 2007, she obtained the Dargut and Milena Kemali specialization scholarship in the field of basic and clinical neurosciences and moved to the laboratory of Isabel Pérez-Otaño, PhD, Centro de Investigacion Medica Aplicada (CIMA), Pamplona, Spain. To acquire new expertise in studying protein-protein interactions, in 2011, Dr. Marcello relocated to the laboratory of Joël Bockaert, PhD and Sylvia Claeysen, PhD, Institut de Genomique Fonctionelle, Montpellier, France, as a Marie Curie fellow, working on the 7FP EU cPADS project on cell permeable peptides as drug delivery system.
Dr. Marcello’s major research achievements are the identification of the synaptic location of ADAM10 and the characterization of the mechanism regulating ADAM10 activity in neurons in physiological and pathological conditions.
First published on: July 9, 2014
Last modified on: April 23, 2019