A\u03b242 pentamers/hexamers are the smallest detectable oligomers in solution

Martin Wolff,Dieter Willbold,Mario Schneider,Luitgard Nagel-Steger,Christina Decker,Aurel Radulescu,Bogdan Barz,Bo Zhang-Haagen,Ralf Biehl,Birgit Strodel

doi:10.1038/s41598-017-02370-3

Abstract

Amyloid β (Aβ) oligomers may play a decisive role in Alzheimer’s disease related neurodegeneration, but their structural properties are poorly understood. In this report, sedimentation velocity centrifugation, small angle neutron scattering (SANS) and molecular modelling were used to identify the small oligomeric species formed by the 42 amino acid residue long isoform of Aβ (Aβ42) in solution, characterized by a sedimentation coefficient of 2.56 S, and a radius of gyration between 2 and 4 nm. The measured sedimentation coefficient is in close agreement with the sedimentation coefficient calculated for Aβ42 hexamers using MD simulations at µM concentration. To the best of our knowledge this is the first report detailing the Aβ42 oligomeric species by SANS measurements. Our results demonstrate that the smallest detectable species in solution are penta- to hexamers. No evidences for the presence of dimers, trimers or tetramers were found, although the existence of those Aβ42 oligomers at measurable quantities had been reported frequently.

Highlights

In the case of Alzheimer’s disease (AD), which is the most common form of dementia worldwide, the accumulation of aggregated amyloid β protein (Aβ) in brain tissue is one of the disease hallmarks[6]
While only one report on a small angle neutron scattering (SANS) study of full length Aβ was found in PubMed[44], which is about the characterization of Aβ40 at acidic solvent conditions, some more reports exist on small angle X-ray scattering (SAXS) studies of Aβ4245, 46
This conclusion emerged from the application of two independent experimental approaches, which are based on different physical principles, sedimentation velocity (SV) analysis and SANS

Summary

Introduction

In the case of Alzheimer’s disease (AD), which is the most common form of dementia worldwide, the accumulation of aggregated amyloid β protein (Aβ) in brain tissue is one of the disease hallmarks[6]. Based on the PICUP technique the involvement of a penta- to hexameric oligomers in the Aβ42 assembly process had been reported in several studies[17,18,19]. Sedimentation velocity (SV) analysis, which is an application of analytical ultracentrifugation (AUC), was shown to be a highly sensitive detection method for trace amounts of aggregates in protein samples. Sedimentation velocity centrifugation allows distinguishing multiple sedimenting species in free solution while maintaining reversibly formed complexes in a bath of their components at all times. This permits the study of self-association as well as heterogeneous protein interactions[36]. Because the two solution-based methods are exploiting different physical properties they are ideally suited to complement each other

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