Abstract

Amyloid-β oligomers (AβOs) self-assemble into polymorphic species with diverse biological activities that are implicated causally to Alzheimer’s disease (AD). Synaptotoxicity of AβO species is dependent on their quaternary structure, however, low-abundance and environmental sensitivity of AβOs in vivo have impeded a thorough assessment of structure–function relationships. We developed a simple biochemical assay to quantify the relative abundance and morphology of cross-linked AβOs. We compared oligomers derived from synthetic Aβ40 (wild-type (WT) Aβ40) and a recombinant source, called Aβ(M1–40). Both peptides assemble into oligomers with common sizes and morphology, however, the predominant quaternary structures of Aβ(M1–40) oligomeric states were more diverse in terms of dispersity and morphology. We identified self-assembly conditions that stabilize high-molecular weight oligomers of Aβ(M1–40) with apparent molecular weights greater than 36 kDa. Given that mixtures of AβOs derived from both peptides have been shown to be potent neurotoxins that disrupt long-term potentiation, we anticipate that the diverse quaternary structures reported for Aβ(M1–40) oligomers using the assays reported here will facilitate research efforts aimed at isolating and identifying common toxic species that contribute to synaptic dysfunction.

Highlights

  • Self-association of the amyloid-β peptide (Aβ) into multimeric oligomers has been linked causally to the progression of Alzheimer’s disease (AD)-related dementia

  • We anticipate that the methods we report to characterize Aβ oligomers (AβOs) morphologies will find general utility in preparing diverse quaternary structure variants that assist in reconciling mechanisms of pathophysiology during AD

  • Previous reports describing WT Aβ42 oligomer self-assembly in the presence of amphiphiles showed that Tween 20 stabilizes high-molecular weight (HMW) oligomers once they form. We found this phenomenon to be consistent for Aβ(M1–40) oligomers, as HMW oligomers were detected at higher levels in samples co-incubated in the presence of Tween 20

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Summary

Introduction

Self-association of the amyloid-β peptide (Aβ) into multimeric oligomers has been linked causally to the progression of Alzheimer’s disease (AD)-related dementia. Diverse biological functions for AβOs has been attributed to the multitude of quaternary structures they adopt in vitro and in vivo [3,4,10,11,14,16,17,18]. Defining these important structure–function relationships has been impeded largely due to a lack of methods to control and isolate specific AβO quaternary structures.

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