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

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

doi:10.1016/j.celrep.2018.12.021

Erik C Gunther, Massimiliano Stagi + Show 19 more

Open Access

https://doi.org/10.1016/j.celrep.2018.12.021

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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.

Highlights

Extensive evidence points to the oligomeric form of b-amyloid peptide (Abo) as the trigger to initiate Alzheimer’s pathology (Citron et al, 1997; Cleary et al, 2005; Hardy and Selkoe, 2002; Kostylev et al, 2015), but clinical measures to reduce brain Ab burden have been therapeutically ineffective (Schneider et al, 2014), inspiring exploration for alternate strategies
Ceftazidime Degradation Yields a Potent Polymeric Abo/PrPC Inhibitor Termed Compound ‘‘Z’’ To search for inhibitors of Abo/PrPC interaction we engaged in a high throughput cell-based screen using stably PrPC-transfected CV-1 cells
Abo prepared from biotinylated synthetic Ab42 peptide associates with these cells in a PrPC-dependent fashion that can be blocked by an antibody (6D11) directed against the Abo-binding domain at PrPC 90-111 (Figures 1A and 1B)

Summary

Introduction

Extensive evidence points to the oligomeric form of b-amyloid peptide (Abo) as the trigger to initiate Alzheimer’s pathology (Citron et al, 1997; Cleary et al, 2005; Hardy and Selkoe, 2002; Kostylev et al, 2015), but clinical measures to reduce brain Ab burden have been therapeutically ineffective (Schneider et al, 2014), inspiring exploration for alternate strategies. Abrogation of Abo/PrPC interaction itself in vivo, genetically (Gimbel et al, 2010; Lauren et al, 2009) or with antibodies directed against the Abo-binding domains on PrPC (Chung et al, 2010; Freir et al, 2011; Klyubin et al, 2014), reverses synaptic degeneration and restores behavioral performance to impaired AD model mice, even as Ab load is unaltered. These data indicate the possibility of disease intervention independently of Abo clearance and identify Abo/PrPC interaction as an opportune nexus for pharmacological intervention after Ab accumulation occurs. Upon Abo association, the unstructured N-terminal PrP domain adopts an a-helical structure, which coincides with the engagement of mGluR5 and consequent synaptotoxic signaling though

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