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; Zaha 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

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, Zaha K. Naderi, Surachai SupattaponeStephen M. Strittmatter

Department of Brain Sciences

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Pages (from-to)	145-158.e8
Journal	Cell Reports
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2018.12.021
State	Published - 2 Jan 2019

Bibliographical note

Publisher Copyright:
© 2018 The Author(s)

Keywords

Alzheimer
Alzheimer's disease
amyloid-beta
antagonist
hydrogel
memory
oligomer
prion
scrapie
synapse loss
β-amyloid

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10.1016/j.celrep.2018.12.021

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Gunther, E. C., Smith, L. M., Kostylev, M. A., Cox, T. O., Kaufman, A. C., Lee, S., Folta-Stogniew, E., Maynard, G. D., Um, J. W., Stagi, M., Heiss, J. K., Stoner, A., Noble, G. P., Takahashi, H., Haas, L. T., Schneekloth, J. S., Merkel, J., Teran, C., Naderi, Z. K., ... Strittmatter, S. M. (2019). Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists. Cell Reports, 26(1), 145-158.e8. https://doi.org/10.1016/j.celrep.2018.12.021

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title = "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 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",

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

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2019",

month = jan,

day = "2",

doi = "10.1016/j.celrep.2018.12.021",

language = "English",

volume = "26",

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Gunther, EC, Smith, LM, Kostylev, MA, Cox, TO, Kaufman, AC, Lee, S, Folta-Stogniew, E, Maynard, GD, Um, JW, Stagi, M, Heiss, JK, Stoner, A, Noble, GP, Takahashi, H, Haas, LT, Schneekloth, JS, Merkel, J, Teran, C, Naderi, ZK, Supattapone, S & Strittmatter, SM 2019, 'Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists', Cell Reports, vol. 26, no. 1, pp. 145-158.e8. https://doi.org/10.1016/j.celrep.2018.12.021

TY - JOUR

T1 - Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists

AU - Gunther, Erik C.

AU - Smith, Levi M.

AU - Kostylev, Mikhail A.

AU - Cox, Timothy O.

AU - Kaufman, Adam C.

AU - Lee, Suho

AU - Folta-Stogniew, Ewa

AU - Maynard, George D.

AU - Um, Ji Won

AU - Stagi, Massimiliano

AU - Heiss, Jacqueline K.

AU - Stoner, Austin

AU - Noble, Geoff P.

AU - Takahashi, Hideyuki

AU - Haas, Laura T.

AU - Schneekloth, John S.

AU - Merkel, Janie

AU - Teran, Christopher

AU - Naderi, Zaha K.

AU - Supattapone, Surachai

AU - Strittmatter, Stephen M.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - 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.

AB - 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.

KW - Alzheimer

KW - Alzheimer's disease

KW - amyloid-beta

KW - antagonist

KW - hydrogel

KW - memory

KW - oligomer

KW - prion

KW - scrapie

KW - synapse loss

KW - β-amyloid

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U2 - 10.1016/j.celrep.2018.12.021

DO - 10.1016/j.celrep.2018.12.021

M3 - Article

C2 - 30605671

AN - SCOPUS:85058797898

SN - 2211-1247

VL - 26

SP - 145-158.e8

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

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