Gunther, EC, Smith, LM, Kostylev, MA, Cox, TO, Kaufman, AC, Lee, S, Folta-Stogniew, E, Maynard, GD, Um, JW, Stagi, M et al (show 11 more authors)
(2019)
Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists.
Cell Reports, 26 (1).
P145-158.E8.
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Prion, Alzheimer, Alzheimer's disease, Amyloid-beta, Oligomer, Scrapie, Antagonist, Hydrogel, Memory, Synapse loss, β-amyloid |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Jan 2019 14:37 |
| Last Modified: | 19 Jan 2023 01:08 |
| DOI: | 10.1016/j.celrep.2018.12.021 |
| Open Access URL: | https://doi.org/10.1016/j.celrep.2018.12.021 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3030543 |
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