A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers

Judith M Silverman, Ebrima Gibbs, Xubiao Peng, Kris M Martens, Claudia Balducci, Jing Wang, Masoud Yousefi, Catherine M Cowan, Guillaume Lamour, Sarah Louadi, Yuxin Ban, Jerome Robert, Sophie Stukas, Gianluigi Forloni, Ging-Yuek R Hsiung, Steven S Plotkin, Cheryl L Wellington, Neil R Cashman

Research output: Contribution to journalArticle

Abstract

Oligomers of amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AβO and inadequate markers for AβO subtypes have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AβOcSNK recognizes ∼50-60 kDa SDS-resistant soluble Aβ assemblages in AD brain and prolongs the lag phase of Aβ aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AβOcSNK in two AD mouse models reduced soluble brain Aβ aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβOcSNK IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AβOcSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.

Original languageEnglish
Pages (from-to)1591-1606
Number of pages16
JournalACS Chemical Neuroscience
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 18 2018

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Poisons
Oligomers
Amyloid
Epitopes
Alzheimer Disease
Lysine
Brain
Agglomeration
Immunoglobulin G
Monomers
Immunization
Asparagine
Molecular Dynamics Simulation
Serine
Fear
Molecular dynamics
Monoclonal Antibodies
Data storage equipment
Peptides
Computer simulation

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A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers. / Silverman, Judith M; Gibbs, Ebrima; Peng, Xubiao; Martens, Kris M; Balducci, Claudia; Wang, Jing; Yousefi, Masoud; Cowan, Catherine M; Lamour, Guillaume; Louadi, Sarah; Ban, Yuxin; Robert, Jerome; Stukas, Sophie; Forloni, Gianluigi; Hsiung, Ging-Yuek R; Plotkin, Steven S; Wellington, Cheryl L; Cashman, Neil R.

In: ACS Chemical Neuroscience, Vol. 9, No. 7, 18.07.2018, p. 1591-1606.

Research output: Contribution to journalArticle

Silverman, JM, Gibbs, E, Peng, X, Martens, KM, Balducci, C, Wang, J, Yousefi, M, Cowan, CM, Lamour, G, Louadi, S, Ban, Y, Robert, J, Stukas, S, Forloni, G, Hsiung, G-YR, Plotkin, SS, Wellington, CL & Cashman, NR 2018, 'A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers', ACS Chemical Neuroscience, vol. 9, no. 7, pp. 1591-1606. https://doi.org/10.1021/acschemneuro.7b00469
Silverman, Judith M ; Gibbs, Ebrima ; Peng, Xubiao ; Martens, Kris M ; Balducci, Claudia ; Wang, Jing ; Yousefi, Masoud ; Cowan, Catherine M ; Lamour, Guillaume ; Louadi, Sarah ; Ban, Yuxin ; Robert, Jerome ; Stukas, Sophie ; Forloni, Gianluigi ; Hsiung, Ging-Yuek R ; Plotkin, Steven S ; Wellington, Cheryl L ; Cashman, Neil R. / A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers. In: ACS Chemical Neuroscience. 2018 ; Vol. 9, No. 7. pp. 1591-1606.
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