Antibody and ligand-based stimulation of ADAM10-mediated shedding of the cellular prion protein as a novel therapeutic strategy in neurodegenerative diseases

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Neurodegenerative diseases, such as Alzheimer’s disease and Creutzfeldt-Jakob disease are characterized by accumulation of misfolded proteins in the brain and this contributes to nerve cell damage, neurodegeneration and death. Current therapeutic approaches are not effective and are limited to symptomatic treatment. In order to define novel therapeutic strategies it is essential that we increase our knowledge on the pathogenesis of these dementias. In its membrane-anchored form, the prion protein binds to misfolded proteins in Alzheimer’s and Creutzfeldt-Jakob disease thereby contributing to nerve cell damage. A soluble form of the prion protein released from the membrane by proteolysis may protect from nerve cell damage. Here we investigate mechanisms underlying proteolytic release of the prion protein. Furthermore, we assess if therapeutic stimulation of this release may decrease nerve cell damage. This project provides novel insights into the pathogenesis of these dementias and may open novel approaches to treat Alzheimer’s and Creutzfeldt-Jakob disease.