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Title: Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity

Abstract

In Alzheimer’s disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβm rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-inducedmore » membrane destabilization and lipid extraction. Here we provide a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer’s disease and other neurodegenerative diseases.« less

Authors:
ORCiD logo [1];  [2];  [3]; ORCiD logo [4];  [5]; ORCiD logo [6]
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  1. Univ. of New Mexico, Albuquerque, NM (United States); Univ. of Colorado, Colorado Springs, CO (United States)
  2. Department of Biomedical Engineering, Texas A&M University, College Station, Texas 77843, United States
  3. Texas A & M Univ., College Station, TX (United States)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Univ. of New Mexico, Albuquerque, NM (United States); National Science Foundation (NSF), Alexandria, VA (United States); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. Univ. of New Mexico, Albuquerque, NM (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Science Foundation (NSF); Univ. of New Mexico; National Institutes of Health (NIH)
OSTI Identifier:
1599452
Alternate Identifier(s):
OSTI ID: 1776772
Report Number(s):
LA-UR-21-22944
Journal ID: ISSN 0743-7463
Grant/Contract Number:  
AC02-06CH11357; CHE-1834750; 1150855; 1605225; 1560058; ASERT-IRACDA-K12-GM088021; UNMCCC-P30-CA118100; UNM-CTSC-UL1-TR001449; NM-INBRE-P20-GM103451; 89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Langmuir
Additional Journal Information:
Journal Volume: 35; Journal Issue: 48; Journal ID: ISSN 0743-7463
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; monolayers; lipids; interfaces; peptides and proteins; membranes; Material science; Alzheimer’s disease; amyloid-beta (Aβ); oligomer; membrane structure; toxicity; membrane-mediated fibrillation; lipid extraction; lipid packing; X-ray scattering

Citation Formats

Vander Zanden, Crystal M., Wampler, Lois, Bowers, Isabella, Watkins, Erik B., Majewski, Jaroslaw, and Chi, Eva Y. Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity. United States: N. p., 2019. Web. doi:10.1021/acs.langmuir.9b02484.
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Vander Zanden, Crystal M., Wampler, Lois, Bowers, Isabella, Watkins, Erik B., Majewski, Jaroslaw, & Chi, Eva Y. Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity. United States. https://doi.org/10.1021/acs.langmuir.9b02484
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Vander Zanden, Crystal M., Wampler, Lois, Bowers, Isabella, Watkins, Erik B., Majewski, Jaroslaw, and Chi, Eva Y. Wed . "Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity". United States. https://doi.org/10.1021/acs.langmuir.9b02484. https://www.osti.gov/servlets/purl/1599452.
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@article{osti_1599452,
title = {Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity},
author = {Vander Zanden, Crystal M. and Wampler, Lois and Bowers, Isabella and Watkins, Erik B. and Majewski, Jaroslaw and Chi, Eva Y.},
abstractNote = {In Alzheimer’s disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβm rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. Here we provide a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer’s disease and other neurodegenerative diseases.},
doi = {10.1021/acs.langmuir.9b02484},
journal = {Langmuir},
number = 48,
volume = 35,
place = {United States},
year = {Wed Sep 11 00:00:00 EDT 2019},
month = {Wed Sep 11 00:00:00 EDT 2019}
}
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https://doi.org/10.1021/acs.langmuir.9b02484
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