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Effects of Prion Protein on Aβ42 and Pyroglutamate-Modified AβpΕ3-42 Oligomerization and Toxicity

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Abstract

Soluble Aβ oligomers are widely recognized as the toxic forms responsible for triggering AD, and Aβ receptors are hypothesized to represent the first step in a neuronal cascade leading to dementia. Cellular prion protein (PrP) has been reported as a high-affinity binder of Aβ oligomers. The interactions of PrP with both Aβ42 and the highly toxic N-truncated pyroglutamylated species (AβpE3-42) are here investigated, at a molecular level, by means of ThT fluorescence, NMR and TEM. We demonstrate that soluble PrP binds both Aβ42 and AβpE3-42, preferentially interacting with oligomeric species and delaying fibril formation. Residue level analysis of Aβ42 oligomerization process reveals, for the first time, that PrP is able to differently interact with the forming oligomers, depending on the aggregation state of the starting Aβ42 sample. A distinct behavior is observed for Aβ42 1-30 region and C-terminal residues, suggesting that PrP protects Aβ42 N-tail from entangling on the mature NMR-invisible fibril, consistent with the hypothesis that Aβ42 N-tail is the locus of interaction with PrP. PrP/AβpE3-42 interactions are here reported for the first time. All interaction data are validated and complemented by cellular tests performed on Wt and PrP-silenced neuronal cell lines, clearly showing PrP dependent Aβ oligomer cell internalization and toxicity. The ability of soluble PrP to compete with membrane-anchored PrP for binding to Aβ oligomers bears relevance for studies of druggable pathways.

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Abbreviations

AD:

Alzheimer disease

PrP:

Cellular prion protein

HM:

High monomer content

LM:

Low monomer content

NMR:

Nuclear magnetic resonance

ThT:

Thioflavin

TEM:

Trasmission electron microscopy

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolimu bromide

DMSO:

Dimethyl sulfoxide

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Funding

This work was supported by the Alzheimer Association (NIRG-14-321500 Grant) and CARIPLO Foundation (2015-0503). LR, KP, ST acknowledge financial support of University of Verona (Bando JOINT Projects 2017, Prof. Michael Assfalg - Dr. Laura Ragona). KP, HM and LR acknowledge Fondazione Antonio De Marco for financial support.

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Authors and Affiliations

  1. Istituto per lo Studio delle Macromolecole (ISMAC), CNR, Milan, Italy

    Katiuscia Pagano, Henriette Molinari, Simona Tomaselli & Laura Ragona

  2. ISMAC, CNR, Genoa, Italy

    Denise Galante & Cristina D’Arrigo

  3. Section of Pharmacology, Department of Internal Medicine, and Center of Excellence for Biomedical research (CEBR), University of Genoa, Genoa, Italy

    Alessandro Corsaro, Mario Nizzari & Tullio Florio

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  1. Katiuscia Pagano
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  2. Denise Galante
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  3. Cristina D’Arrigo
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  4. Alessandro Corsaro
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  5. Mario Nizzari
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  6. Tullio Florio
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  7. Henriette Molinari
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  8. Simona Tomaselli
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  9. Laura Ragona
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Corresponding authors

Correspondence to Simona Tomaselli or Laura Ragona.

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Pagano, K., Galante, D., D’Arrigo, C. et al. Effects of Prion Protein on Aβ42 and Pyroglutamate-Modified AβpΕ3-42 Oligomerization and Toxicity. Mol Neurobiol 56, 1957–1971 (2019). https://doi.org/10.1007/s12035-018-1202-x

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  • DOI: https://doi.org/10.1007/s12035-018-1202-x

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