Amyloid β 1-42 Can Form Ion Channels as Small as Gramicidin in Model Lipid Membranes

TL;DR

This study shows that Aβ1-42 oligomers can form small ion channels in lipid membranes, similar to gramicidin, contributing to Alzheimer's disease cytotoxicity.

Contribution

The study demonstrates that Aβ1-42 oligomers can form ion channels as small as gramicidin in model membranes, offering new insights into Alzheimer's disease pathology.

Findings

Aβ1-42 oligomers induce small ion channels in lipid membranes with an average inner diameter smaller than 5 Å.

These channels are highly dynamic, with short retaining times in the membranes.

The findings support the Aβ channelopathy hypothesis in Alzheimer's disease.

Abstract

The amyloid-beta 1-42 (Aβ1-42) oligomers are the most cytotoxic species of the amyloid family and play a key role in the pathology of Alzheimer’s Disease (AD). They have been shown to damage cellular membranes, but the exact mechanism is complex and not well understood. Multiple routes of membrane damage have been proposed, including the formation of pores and ion channels. In this work, we study the membrane damage induced by Aβ1-42 oligomers using black lipid membrane (BLM) electrophysiology and compare their action with gramicidin, known to form ion channels. Our data show that Aβ1-42 oligomers can induce a variety of damage in the lipid membranes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and cholesterol (CHOL), including small ion channels, similar to the gramicidin channels, with an average inner diameter smaller than 5 Å. These channels have a short retaining time in lipid membranes, suggesting that they are highly dynamic. Our studies provide new insights into the mechanism of membrane damage caused by Aβ1-42 oligomers and extend the current perception of the Aβ channelopathy hypothesis. It provides a more in-depth understanding of the molecular mechanism by which small Aβ oligomers induce cytotoxicity by interacting with lipid membranes in AD.

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