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Apolipoprotein A-I Mimetic 4F Peptide Generates Amyloid Cytotoxins by Forming Hetero-oligomers with β-amyloid

Bikash Ranjan Sahoo, Michael E. Bekier II, Zichen Liu, Vojc Kocman, Andrea K. Stoddard, G. M. Anantharamaiah, James Nowick, Carol A. Fierke, Yanzhuang Wang, View ORCID ProfileAyyalusamy Ramamoorthy
doi: https://doi.org/10.1101/722983
Bikash Ranjan Sahoo
Biophysics and Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1055, USA
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Michael E. Bekier
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1055, USA
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Zichen Liu
Biophysics and Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1055, USA
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Vojc Kocman
Biophysics and Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1055, USA
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Andrea K. Stoddard
Biophysics and Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1055, USA
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G. M. Anantharamaiah
Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, Alabama, 35294, USA
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James Nowick
Department of Chemistry, University of California-Irvine, Irvine, CA 92697-2025, USA
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Carol A. Fierke
Department of Chemistry, University of Texas A&M, College Station, TX 77843-3255, USA
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Yanzhuang Wang
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1055, USA
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Ayyalusamy Ramamoorthy
Biophysics and Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1055, USA
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  • ORCID record for Ayyalusamy Ramamoorthy
  • For correspondence: ramamoor@umich.edu
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Abstract

Apolipoproteins are involved in pathological conditions of Alzheimer’s disease (AD), truncated apolipoprotein fragments and β-amyloid (Aβ) peptides coexist as neurotoxic heteromers within the plaques. Therefore, it is important to investigate these complexes at the molecular level to better understand their properties and roles in the pathology of AD. Here, we present a mechanistic insight into such heteromerization using a structurally homologue apolipoprotein fragment of apoA-I (4F) complexed with Aβ(M1-42) and characterize their toxicity. The 4F peptide slows down the aggregation kinetics of Aβ(M1-42) by constraining its structural plasticity. NMR and CD experiments identified 4F-Aβ(M1-42) heteromers as being comprised of unstructured Aβ(M1-42) and helical 4F. A uniform ≈2-fold reduction in Aβ42 15N/1H NMR signal intensities with no observable chemical shift perturbation indicated the formation of a large complex, which was further confirmed by diffusion NMR experiments. Microsecond scale atomistic molecular dynamics simulations showed that 4F interaction with Aβ(M1-42) is electrostatically driven and induces unfolding of Aβ(M1-42). Neurotoxicity profiling of Aβ(M1-42) complexed with 4F confirms a significant reduction in cell-viability and neurite growth. The molecular architecture of heteromerization between 4F and Aβ(M1-42) discovered in this study provides evidence towards our understanding of the role of apolipoproteins or their truncated fragments in exacerbating AD pathology.

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Posted August 04, 2019.
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Apolipoprotein A-I Mimetic 4F Peptide Generates Amyloid Cytotoxins by Forming Hetero-oligomers with β-amyloid
Bikash Ranjan Sahoo, Michael E. Bekier II, Zichen Liu, Vojc Kocman, Andrea K. Stoddard, G. M. Anantharamaiah, James Nowick, Carol A. Fierke, Yanzhuang Wang, Ayyalusamy Ramamoorthy
bioRxiv 722983; doi: https://doi.org/10.1101/722983
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Apolipoprotein A-I Mimetic 4F Peptide Generates Amyloid Cytotoxins by Forming Hetero-oligomers with β-amyloid
Bikash Ranjan Sahoo, Michael E. Bekier II, Zichen Liu, Vojc Kocman, Andrea K. Stoddard, G. M. Anantharamaiah, James Nowick, Carol A. Fierke, Yanzhuang Wang, Ayyalusamy Ramamoorthy
bioRxiv 722983; doi: https://doi.org/10.1101/722983

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