Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies

The prion protein (PrPC) is a central player in neurodegenerative diseases, such as prion diseases or Alzheimer’sdisease. In contrast to disease-promoting cell surface PrPC, extracellular fragments act neuroprotective by blockingneurotoxic disease-associated protein conformers. Fittingly, PrPC release by the metalloprotease ADAM10represents a protective mechanism. We used biochemical, cell biological, morphological, and structural methodsto investigate mechanisms stimulating this proteolytic shedding. Shed PrP negatively correlates with prion conversionand is markedly redistributed in murine brain in the presence of prion deposits or amyloid plaques, indicatinga sequestrating activity. PrP-directed ligands cause structural changes in PrPC and increased shedding in cellsand organotypic brain slice cultures. As an exception, some PrP-directed antibodies targeting repetitive epitopesdo not cause shedding but surface clustering, endocytosis, and degradation of PrPC. Both mechanisms may contributeto beneficial actions described for PrP-directed ligands and pave the way for new therapeutic strategiesagainst currently incurable neurodegenerative diseases