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Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer
Journal article   Open access   Peer reviewed

Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer

Rachit Pandey, Thomas Ruggiero, Brian Andrews and Brigita Urbanc
ACS chemical neuroscience, Forthcoming
21 May 2026
DOI: https://doi.org/10.1021/acschemneuro.5c00942
PMID: 42168823
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
url
https://doi.org/10.1021/acschemneuro.5c00942View
Published, Version of Record (VoR) Open Access via Drexel Libraries Read and Publish Program 2026 Open CC BY V4.0

Abstract

Lipid bilayer Amyloid β-protein (Aβ) Alzheimer’s disease Molecular Dynamics Cholesterol
The leading Alzheimer's disease (AD) hypothesis posits that oligomers formed by amyloid β-protein (Aβ), in particular 42-residue-long Aβ42, interact with a cellular membrane, causing a cascade of events leading to neurodegeneration. The modes of Aβ42-lipid interactions are not well understood. Here, we use explicit-solvent all-atom molecular dynamics (MD) to demonstrate that Aβ42 monomers interact with lipids differently than Aβ42 dimers. In our simulations, lipids in the absence and presence of Aβ42 form a lipid bilayer with a cholesterol-rich domain, resembling a lipid raft. Whereas lipids stabilize the Aβ42 monomer structure, they partially destabilize Aβ42 dimers. Unlike monomers, which interact exclusively with solvent-exposed lipid tails on one side of a bilayer, dimers exhibit additional modes of interactions with lipids, including spontaneous insertion into the cholesterol-rich domain of a bilayer and carpeting, thereby disrupting the lipid bilayer structure. Our findings provide a mechanistic explanation for why Aβ42 monomers are nontoxic and reveal that Aβ42 oligomer-induced toxicity emerges already at the stage of Aβ42 dimer formation.

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