The cellular prion protein traps Alzheimer's A in an oligomeric form and disassembles amyloid fibers

*School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK
The FASEB Journal (Impact Factor: 5.04). 01/2013; 27(5). DOI: 10.1096/fj.12-222588
Source: PubMed


There is now strong evidence to show that the presence of the cellular prion protein (PrP(C)) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP(C) and Aβ and discover that substoichiometric amounts of PrP(C), as little as 1/20, relative to Aβ will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrP(C). Electron microscopy indicates PrP(C) is able to trap Aβ in an oligomeric form. Unlike fibers, this oligomeric Aβ contains antiparallel β sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrP(C), notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrP(C) to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrP(C) might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrP(C) that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.-Younan, N. D., Sarell, C. J., Davies, P., Brown, D. R., Viles, J. H. The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers.

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Available from: John H Viles, Mar 04, 2014
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    • "One proposed mechanism is that oligomeric aggregates are able to degrade the barrier properties of membranes, resulting in calcium fluxes (Demuro et al., 2005; Yoshiike et al., 2007). By contrast, there is also evidence for pathogenic mechanisms involving binding to specific cell surface receptors – an example being the prion protein (Barry et al., 2011; Kudo et al., 2011; Lauren et al., 2009; Younan et al., 2013). However, there are many more aspects to Aβ toxicity and of particular interest is the pathogenic role of redox-active metal cofactors in generating oxidative stress in the brain. "
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    ABSTRACT: Metals including iron are present at high concentrations in amyloid plaques in patients with Alzheimer's disease where they are also thought to be co-factors in generating oxidative stress and modulating amyloid formation. In this study we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and Aβ is specific and is not seen for other aggregation-prone polypeptides. The interaction with iron is likely important in the dimerisation of Aβ and is mediated by three N-terminal histidines. Transgenic fly lines systematically expressing all combinations of His>Ala substitutions in Aβ were generated and were used to study the pathological role of these residues. Developmental eye phenotypes, longevity and histological examinations indicate that the N-terminal histidines have distinct position-dependent and -independent mechanisms. The former mediate the toxic effects of metals and Aβ aggregation under non-oxidising conditions and the latter are relevant under oxidising conditions. Understanding how Aβ mediates neurotoxic effects in vivo will help us better target pathological pathways using aggregation-blockers and metal-modifying agents. © 2015. Published by The Company of Biologists Ltd.
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    • "Although some downstream toxicity mechanisms have been tested in AD (Schilling et al., 2008; Lopes et al., 2010), it is still far from its complete understanding. The idea of close relationship between different protein misfolding related diseases is stronger every day as proven by some recent works showing PrP mediated A␤ toxicity (Larson et al., 2012; Younan et al., 2013; Wang et al., 2013) and could help to understand the cross-seeding phenomenon as the one shown by Morales and collaborators where prion inoculation in an AD model accelerated both pathologies (Morales et al., 2010, 2013). "
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    ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.
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    • "The associations of PrPC with neuropathology apart from the conventional prion diseases (Jiménez-Huete et al., 1998; Ferrer et al., 2001; Voigtländer et al., 2001; Checler and Vincent, 2002; Aguzzi and Haass, 2003; Rezaie et al., 2005; Schwarze-Eicker et al., 2005; Ramljak et al., 2008). Of interest to us are the controversial issues in the literature linking Aβ oligomers and PrPC (Laurén et al., 2009; Nygaard and Strittmatter, 2009; Gunther and Striitmatter, 2010; Kessels et al., 2010; Barry et al., 2011; Saijo et al., 2011; Larson et al., 2012; Um et al., 2012; Chen et al., 2013; Kudo et al., 2013; Whitehouse et al., 2013; Younan et al., 2013). A few specific examples to make the point: Kudo et al. showed that Prnp (-/-) mice are resistant to the neurotoxic effect of oligomeric Aβ in vivo and in vitro (Kudo et al., 2013). "
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