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A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers
journal contribution
posted on 2018-04-04, 00:00 authored by 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. CashmanOligomers 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.