Description: Role of Oxidized Gly25, Gly29, and Gly33 Residues on the Interactions of Aβ 1

This title appears in the Scientific Report : 2020

Role of Oxidized Gly25, Gly29, and Gly33 Residues on the Interactions of Aβ 1–42 with Lipid Membranes

Oxidative stress is known to play an important role in the pathogenesis of Alzheimer's disease. Moreover, it is becoming increasingly evident that the plasma membrane of neurons plays a role in modulating the aggregation and toxicity of Alzheimer's amyloid-β peptide (Aβ). In this study, th...

Personal Name(s):	Fatafta, Hebah
	Poojari, Chetan / Sayyed-Ahmad, Abdallah / Strodel, Birgit / Owen, Michael (Corresponding author)
Contributing Institute:	Strukturbiochemie; ICS-6
Published in:	ACS chemical neuroscience, 11 (2020) 4, S. 535-548
Imprint:	Washington, DC ACS Publ. 2020
DOI:	10.1021/acschemneuro.9b00558
PubMed ID:	31939658
Document Type:	Journal Article
Research Program:	Physical Basis of Diseases
Link:	Published on 2020-01-15. Available in OpenAccess from 2021-01-15. Restricted Published on 2020-01-15. Available in OpenAccess from 2021-01-15. Restricted
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1021/acschemneuro.9b00558 in citations.
Please use the identifier: http://hdl.handle.net/2128/24627 in citations.

Oxidative stress is known to play an important role in the pathogenesis of Alzheimer's disease. Moreover, it is becoming increasingly evident that the plasma membrane of neurons plays a role in modulating the aggregation and toxicity of Alzheimer's amyloid-β peptide (Aβ). In this study, the combined and interdependent effects of oxidation and membrane interactions on the 42 residues long Aβ isoform are investigated using molecular simulations. Hamiltonian replica exchange molecular dynamics simulations are utilized to elucidate the impact of selected oxidized glycine residues of Aβ42 on the interactions of the peptide with a model membrane comprised of 70% POPC, 25% cholesterol, and 5% of the ganglioside GM1. The main findings are that, independent of the oxidation state, Aβ prefers binding to GM1 over POPC, which is further enhanced by the oxidation of Gly29 and Gly33 and reduced the formation of β-sheet. Our results suggest that the differences observed in Aβ42 conformations and its interaction with a lipid bilayer upon oxidation originate from the position of the oxidized Gly residue with respect to the hydrophobic sequence of Aβ42 involving the Gly29-XXX-Gly33-XXX-Gly37 motif and from specific interactions between the peptide and the terminal sugar groups of GM1.