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

Cellular prion protein (PrP) binds the scrapie conformation of PrP (PrP) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrP interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrP with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrP 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 PrP prevents Aβo/PrP-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrP production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1ΔE9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrP-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.