Issue 27, 2017

Glucose directs amyloid-beta into membrane-active oligomers

Abstract

Oligomeric amyloid-β 1–42 (Aβ-42) peptides are considered to be the most toxic species connected to the occurrence of Alzheimer's disease. However, not all aggregation conditions promote oligomer formation in vitro, raising the question whether oligomer formation in vivo also requires a specific suitable cellular environment. We recently found that interaction with neuronal membranes initiates aggregation of Aβ-42 and neuronal uptake. Our data suggest that small molecules in the extracellular space can facilitate the formation of membrane-active Aβ-42 oligomers. We analyzed the early stage of Aβ-42 aggregation in the presence of glucose and sucrose and found that these sugars strongly favor Aβ-42 oligomer formation. We characterized oligomers by dynamic light scattering, atomic force microscopy, immuno-transmission electron microscopy and fluorescence cross correlation spectroscopy. We found that Aβ-42 spontaneously and rapidly forms low molecular weight oligomers in the presence of sugars. Slightly acidic pH (6.7–7) greatly favors oligomer formation when compared to the extracellular physiological pH (7.4). Circular dichroism demonstrated that these Aβ-42 oligomers did not adopt a β-sheet structure. Unstructured oligomeric Aβ-42 interacted with membrane bilayers of giant unilamellar vesicles (GUV) and neuronal model cells, facilitated cellular uptake of Aβ-42, and inhibition of mitochondrial activity. Our data therefore suggest that elevated concentrations of glucose within the range observed in diabetic individuals (10 mM) facilitate the formation of membrane-active Aβ-42 oligomers.

Graphical abstract: Glucose directs amyloid-beta into membrane-active oligomers

Supplementary files

Article information

Article type
Paper
Submitted
01 May 2017
Accepted
23 Jun 2017
First published
26 Jun 2017

Phys. Chem. Chem. Phys., 2017,19, 18036-18046

Glucose directs amyloid-beta into membrane-active oligomers

N. Kedia, M. Almisry and J. Bieschke, Phys. Chem. Chem. Phys., 2017, 19, 18036 DOI: 10.1039/C7CP02849K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements