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

Erik C Gunther; Levi M Smith; Mikhail A Kostylev; Timothy O Cox; Adam C Kaufman; Suho Lee; Ewa Folta-Stogniew; George D Maynard; Ji Won Um; Massimiliano Stagi; Jacqueline K Heiss; Austin Stoner; Geoff P Noble; Hideyuki Takahashi; Laura T Haas; John S Schneekloth; Janie Merkel; Christopher Teran; Zahra K Naderi; Surachai Supattapone; Stephen M Strittmatter

doi:10.1016/j.celrep.2018.12.021

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.

Authors

Erik C Gunther¹, Levi M Smith², Mikhail A Kostylev¹, Timothy O Cox¹, Adam C Kaufman¹, Suho Lee¹, Ewa Folta-Stogniew³, George D Maynard⁴, Ji Won Um¹, Massimiliano Stagi¹, Jacqueline K Heiss¹, Austin Stoner¹, Geoff P Noble⁵, Hideyuki Takahashi¹, Laura T Haas¹, John S Schneekloth⁶, Janie Merkel⁶, Christopher Teran¹, Zahra K Naderi¹, Surachai Supattapone⁵, Stephen M Strittmatter⁷

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: stephen.strittmatter@yale.edu.

Abstract

Cellular prion protein (PrP^C) binds the scrapie conformation of PrP (PrP^Sc) 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^C interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrP^C with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrP^C 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^C prevents Aβo/PrP^C-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrP^Sc 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^C-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / physiopathology*
Animals
Mice
Mice, Transgenic
Prion Proteins / antagonists & inhibitors*
Signal Transduction

Substances

Prion Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding