Stabilization of a Membrane-Associated Amyloid-beta Oligomer for Its Validation in Alzheimer's Disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Frontiers in Molecular Biosciences Année : 2018

Stabilization of a Membrane-Associated Amyloid-beta Oligomer for Its Validation in Alzheimer's Disease

Résumé

We have recently reported on the preparation of a membrane-associated beta-barrel Pore-Forming Abeta42 Oligomer (betaPFOAbeta42). It corresponds to a stable and homogeneous Abeta42 oligomer that inserts into lipid bilayers as a well-defined pore and adopts a specific structure with characteristics of a beta-barrel arrangement. As a follow-up of this work, we aim to establish betaPFOAbeta42's relevance in Alzheimer's disease (AD). However, betaPFOAbeta42 is formed under dodecyl phosphocholine (DPC) micelle conditions-intended to mimic the hydrophobic environment of membranes-which are dynamic. Consequently, dilution of the betaPFOAbeta42/DPC complex in a detergent-free buffer leads to dispersion of the DPC molecules from the oligomer surface, leaving the oligomer without the hydrophobic micelle belt that stabilizes it. Since dilution is required for any biological test, transfer of betaPFOAbeta42 from DPC micelles into another hydrophobic biomimetic membrane environment, that remains associated with betaPFOAbeta42 even under high dilution conditions, is a requisite for the validation of betaPFOAbeta42 in AD. Here we describe conditions for exchanging DPC micelles with amphipols (APols), which are amphipathic polymers designed to stabilize membrane proteins in aqueous solutions. APols bind in an irreversible but non-covalent manner to the hydrophobic surface of membrane proteins preserving their structure even under extreme dilution conditions. We tested three types of APols with distinct physical-chemical properties and found that the betaPFOAbeta42/DPC complex can only be trapped in non-ionic APols (NAPols). The characterization of the resulting betaPFOAbeta42/NAPol complex by biochemical tools and structural biology techniques allowed us to establish that the oligomer structure is maintained even under high dilution. Based on these findings, this work constitutes a first step towards the in vivo validation of betaPFOAbeta42 in AD.

Domaines

Matériaux

Dates et versions

hal-03160504 , version 1 (05-03-2021)

Identifiants

Citer

Montserrat Serra-Batiste, James Tolchard, Fabrice Giusti, Manuela Zoonens, Natalia Carulla. Stabilization of a Membrane-Associated Amyloid-beta Oligomer for Its Validation in Alzheimer's Disease. Frontiers in Molecular Biosciences, 2018, 5, pp.38-38. ⟨10.3389/fmolb.2018.00038⟩. ⟨hal-03160504⟩

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