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

神经退行性疾病，如阿尔茨海默病和克雅氏病的特征在于错误折叠的蛋白质在脑中的积累，这有助于神经细胞损伤、神经变性和死亡。目前的治疗方法是无效的，仅限于对症治疗。为了确定新的治疗策略，我们必须增加对这些痴呆症发病机制的了解。朊病毒蛋白以其膜锚定形式与阿尔茨海默病和克雅氏病中的错误折叠蛋白结合，从而导致神经细胞损伤。朊病毒蛋白的可溶形式通过蛋白水解从细胞膜中释放出来，可以保护神经细胞免受损伤。在这里，我们调查的机制，蛋白水解释放的朊病毒蛋白。此外，我们评估这种释放的治疗刺激是否可以减少神经细胞损伤。该项目为这些痴呆症的发病机制提供了新的见解，并可能开辟治疗阿尔茨海默病和克雅氏病的新方法。

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.