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. 2018 Aug 24;293(34):13090-13099.
doi: 10.1074/jbc.RA118.003319. Epub 2018 Jun 10.

Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease

Nadine D Younan  1 , Ko-Fan Chen  2 , Ruth-Sarah Rose  1 , Damian C Crowther  3 , John H Viles  4
Affiliations

Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease

Nadine D Younan et al. J Biol Chem. .

Abstract

The cellular prion protein (PrPC) can act as a cell-surface receptor for β-amyloid (Aβ) peptide; however, a role for PrPC in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrPC in the Drosophila brain. We found that co-expression of Aβ and PrPC significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain. In contrast, under the same conditions, expression of Aβ or PrPC individually did not lead to these phenotypic changes. In vitro studies revealed that substoichiometric amounts of PrPC trap Aβ as oligomeric assemblies and fragment-preformed Aβ fibers. The ability of membrane-anchored PrPC to trap Aβ as cytotoxic oligomers at the membrane surface and fragment inert Aβ fibers suggests a mechanism by which PrPC exacerbates Aβ deposition and pathogenic phenotypes in the fly, supporting a role for PrPC in AD. This study provides a second animal model linking PrPC expression with Aβ toxicity and supports a role for PrPC in AD pathogenesis. Blocking the interaction of Aβ and PrPC represents a potential therapeutic strategy.

Keywords: Alzheimer's disease; Drosophila; amyloid-beta (AB); animal model; circadian rhythm; fibril; neurodegenerative disease; oligomer; prion; protein misfolding.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Aβ and PrPC interact to reduce longevity in Drosophila. A–C, the effects on longevity when co-expressing PrPC with Aβ isoforms: Aβ40 (A), Aβ42 (B), and Aβ42Arc (C). The co-expression of PrP with Aβ (red), PrP only (orange), Aβ only (blue), and nontransgenic control flies 51D/51D (black) is shown. Co-expression of Aβ with PrP causes a significant reduction in longevity particularly for Aβ42 and Aβ42Arc flies. Each survival assay used 100 flies repeated four times; in total 400 flies/genotype were used. D, scatter plot showing the median survival of each vial of 10 flies, with 40 vials for each genotype. *, p < 0.05; ns, no significant difference.
Figure 2.
Figure 2.
Aβ and PrPC interact to degrade circadian rhythmicity in a Drosophila model. A–D, four actograms showing the average locomotor activity of a group of typically 16 Drosophila males for each genotype. A, WT (51D/51D). B, PrP only. C, Aβ42 only. D, PrP + Aβ42. Flies were entrained in a 12-h light:12-h dark cycle up to day 12 and thereafter maintained in continuous darkness. The data are presented for days 12–18. E, rhythmicity statistic for the indicated genotypes and n number: 51D/51D, n = 35; 51D/Aβ40, n = 42; 51D/Aβ42, n = 38; 51D/Aβ42Arc, n = 51; 51D/PrP, n = 44; PrP/Aβ40, n = 41; PrP/Aβ42, n = 49; and PrP/Aβ42Arc, n = 20. Loss of rhythmicity is significant for the PrP + Aβ crossed flies. ***, p < 0.001; **, p < 0.01. F, the percentage of flies/genotype that retained circadian rhythmicity. The Aβ + PrP crossed flies (red shades) have marked loss in rhythmicity. The y axis shows the percentage of rhythmicity >1.5.
Figure 3.
Figure 3.
PrPC promotes Aβ accumulation in Drosophila brain by direct interaction. A, a comparison of Aβ-expressing flies with PrP (top row) or without PrP co-expression (bottom row). Anti-Aβ antibody (green) was used to identify all Aβ deposits, and an anti-pigment dispersing factor antibody (magenta) stains throughout fly brain including central brain (CB) and its optic lobe (OL); each image box is 250 × 250 μm. B, a plot presenting the fraction of Aβ positive area for Drosophila brain sections, 10 flies/construct. C, co-immunoprecipitation indicates direct Aβ–PrP interaction in the fly brain extracts. SDS Western blotting was carried out using SE16, the anti-Aβ antibody; the complex was precipitated using Sha31, the anti-PrP antibody. The Western blotting shown is for Aβ42–PrP and Aβ42Arc–PrP co-expressing flies, together with control flies expressing single transgenes.
Figure 4.
Figure 4.
In vitro Aβ42 and Aβ42Arc fiber formation inhibited by the presence of PrPC. A and B, fiber formation kinetics of Aβ42 and Aβ42Arc monitored by ThT fluorescence; in the absence of PrPC (blue) or in the presence of 0.5 molar equivalents of PrPC (red) and 1 molar equivalents of PrPC added to mature fibers (black). The arrow highlights the point at which PrPC was added to mature Aβ fibers. C and D, negative stain TEM images of Aβ42 fibers (C) and Aβ42Arc fibers (D). E and F, Aβ42 incubated in the presence of 0.5 molar equivalent of PrP(23–231) (E) and Aβ42Arc with PrPC (F). Scale bar, 100 nm.
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References

    1. Prince M., Bryce R., Albanese E., Wimo A., Ribeiro W., and Ferri C. P. (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dementia 9, 63–75 10.1016/j.jalz.2012.11.007 - DOI - PubMed
    1. Walsh D. M., Klyubin I., Fadeeva J. V., Cullen W. K., Anwyl R., Wolfe M. S., Rowan M. J., and Selkoe D. J. (2002) Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 10.1038/416535a - DOI - PubMed
    1. Lambert M. P., Barlow A. K., Chromy B. A., Edwards C., Freed R., Liosatos M., Morgan T. E., Rozovsky I., Trommer B., Viola K. L., Wals P., Zhang C., Finch C. E., Krafft G. A., and Klein W. L. (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 95, 6448–6453 10.1073/pnas.95.11.6448 - DOI - PMC - PubMed
    1. Lesné S., Koh M. T., Kotilinek L., Kayed R., Glabe C. G., Yang A., Gallagher M., and Ashe K. H. (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 10.1038/nature04533 - DOI - PubMed
    1. Yankner B. A., and Lu T. (2009) Amyloid β-protein toxicity and the pathogenesis of Alzheimer disease. J. Biol. Chem. 284, 4755–4759 10.1074/jbc.R800018200 - DOI - PMC - PubMed

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