Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists.

ABSTRACT: Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric ?-amyloid peptide (A?o) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with A?o. A polymeric degradant of an antibiotic targets A?o binding sites on PrPC with low nanomolar affinity and prevents A?o-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly [4-styrenesulfonic acid-co-maleic acid], PSCMA) origin. Association of PSCMA with PrPC prevents A?o/PrPC-hydrogel formation, blocks A?o binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1?E9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.

SUBMITTER: Gunther EC 

PROVIDER: S-EPMC6358723 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature