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. 2016 Feb 16:6:20997.
doi: 10.1038/srep20997.

Amyloid-β peptides in interaction with raft-mime model membranes: a neutron reflectivity insight

Valeria Rondelli  1 , Paola Brocca  1 , Simona Motta  1 , Massimo Messa  2 , Laura Colombo  2 , Mario Salmona  2 , Giovanna Fragneto  3 , Laura Cantù  1 , Elena Del Favero  1
Affiliations

Amyloid-β peptides in interaction with raft-mime model membranes: a neutron reflectivity insight

Valeria Rondelli et al. Sci Rep. .

Abstract

The role of first-stage β-amyloid aggregation in the development of the Alzheimer disease, is widely accepted but still unclear. Intimate interaction with the cell membrane is invoked. We designed Neutron Reflectometry experiments to reveal the existence and extent of the interaction between β-amyloid (Aβ) peptides and a lone customized biomimetic membrane, and their dependence on the aggregation state of the peptide. The membrane, asymmetrically containing phospholipids, GM1 and cholesterol in biosimilar proportion, is a model for a raft, a putative site for amyloid-cell membrane interaction. We found that the structured-oligomer of Aβ(1-42), its most acknowledged membrane-active state, is embedded as such into the external leaflet of the membrane. Conversely, the Aβ(1-42) unstructured early-oligomers deeply penetrate the membrane, likely mimicking the interaction at neuronal cell surfaces, when the Aβ(1-42) is cleaved from APP protein and the membrane constitutes a template for its further structural evolution. Moreover, the smaller Aβ(1-6) fragment, the N-terminal portion of Aβ, was also used. Aβ N-terminal is usually considered as involved in oligomer stabilization but not in the peptide-membrane interaction. Instead, it was seen to remove lipids from the bilayer, thus suggesting its role, once in the whole peptide, in membrane leakage, favouring peptide recruitment.

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Figures

Figure 1
Figure 1. Scheme of the neutron reflectometry experimental set-up.
Figure 2
Figure 2. Multiple-contrast analysis of Membrane A at 22 °C.
Spectra (left panel) and contrast profiles (right panel) in: H2O (green dots), D2O (blue triangles) and 4 MW (red crosses). Left panel: symbols mark the experimental spectra, lines the multi-contrast combined fit. R is the normalized reflected intensity. Right panel: over contrast profiles, vertical dashed lines are drawn to guide the eye to approximately identify 7 regions, referring to different portions of the reflecting system: the silicon oxide (1), a water layer (2), the inner hydrophilic layer (3), the inner hydrophobic layer (4), the outer hydrophobic layer (5), the outer hydrophilic layer (6) and the bulk solvent (7).
Figure 3
Figure 3
Neutron reflectivity spectra of membranes A and B before (black, triangles) and after (red, dots) the interaction with Aβ1-42 structured-oligomers (panel a) and early-oligomers (panel c) respectively, in H2O at 22 °C. Lines are the best fit to the experimental data. Panel (b) and panel (d) report the contrast profiles corresponding to spectra in panel (a) and panel (c), respectively (same color code).
Figure 4
Figure 4
Neutron reflectivity spectra (left panel) and contrast profiles (right panel) of membrane C before (black, triangles) and after (red, dots) the interaction with the N-terminus Aβ1-6, in H2O at 22 °C.
Figure 5
Figure 5
Pictorial sketch of a biomimetic membrane interacting with Aβ peptides: (A) Aβ peptides in the membrane-active structured-oligomer state (Membrane filling); (B) Aβ peptides in the monomeric state: (B1) monomers embroider the membrane and (B2) peptide oligomerization takes place next to membrane surface (Membrane digging); (C) membrane interacts with the N-terminal Aβ1-6 sequence (Membrane leakage).
See this image and copyright information in PMC

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