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Published, Version of Record (VoR) Open Access via Drexel Libraries Read and Publish Program 2026 Open CC BY V4.0
Journal article
Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer
ACS chemical neuroscience, Forthcoming
21 May 2026
PMID: 42168823
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
Abstract
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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Details
- Title
- Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer
- Creators
- Rachit Pandey - Drexel UniversityThomas Ruggiero - Drexel UniversityBrian Andrews - Drexel UniversityBrigita Urbanc (Corresponding Author) - Drexel University
- Publication Details
- ACS chemical neuroscience, Forthcoming
- Publisher
- ACS Publications
- Number of pages
- 17
- Grant note
- Office of Advanced Cyberinfrastructure: OAC-1919691
This work has been supported by the National Science Foundation through grant number OAC-1919691. MD simulations were performed on hardware supported by Drexel's University Research Computing Facility and on Bridges-2 at Pittsburgh Supercomputing Center through allocation BIO250006 from the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program, which is supported by National Science Foundation grants #2138259, #2138286, #2138307, #2137603, and #2138296.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:001774216700001
- Other Identifier
- 991022182975604721
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- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences