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

  • Cell Rep. 2019 Jan 2;26(1):145-158.e8. doi: 10.1016/j.celrep.2018.12.021.
Erik C Gunther  1 ,  Levi M Smith  2 ,  Mikhail A Kostylev  1 ,  Timothy O Cox  1 ,  Adam C Kaufman  1 ,  Suho Lee  1 ,  Ewa Folta-Stogniew  3 ,  George D Maynard  4 ,  Ji Won Um  1 ,  Massimiliano Stagi  1 ,  Jacqueline K Heiss  1 ,  Austin Stoner  1 ,  Geoff P Noble  5 ,  Hideyuki Takahashi  1 ,  Laura T Haas  1 ,  John S Schneekloth  6 ,  Janie Merkel  6 ,  Christopher Teran  1 ,  Zahra K Naderi  1 ,  Surachai Supattapone  5 ,  Stephen M Strittmatter  7
Affiliations
  • 1. Cellular Neuroscience, Neurodegeneration, Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA.
  • 2. Cellular Neuroscience, Neurodegeneration, Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 3. W.M. Keck Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06511, USA.
  • 4. ReNetX Bio, Inc., New Haven, CT 06510, USA.
  • 5. Departments of Biochemistry, Cell Biology, and Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
  • 6. Yale Center for Molecular Discovery, Yale University, 600 West Campus Drive, West Haven, CT 06516, USA.
  • 7. Cellular Neuroscience, Neurodegeneration, Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA. Electronic address: [email protected].
PMID: 30605671 DOI: 10.1016/j.celrep.2018.12.021
Abstract

Cellular Prion Protein (PrPC) binds the scrapie conformation of PrP (PrPSc) 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 PrPC interaction with Aβo. A polymeric degradant of an Antibiotic targets Aβo binding sites on PrPC with low nanomolar affinity and prevents Aβo-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 Aβo/PrPC-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrPSc 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 PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.

Keywords
Alzheimer; Alzheimer’s disease; amyloid-beta; antagonist; hydrogel; memory; oligomer; prion; scrapie; synapse loss; β-amyloid.
Products