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GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers

Dong Yan Zhang, Jian Wang, Rebecca M. Fleeman, Madison K. Kuhn, Matthew T. Swulius, Elizabeth A. Proctor, View ORCID ProfileNikolay V. Dokholyan
doi: https://doi.org/10.1101/2021.07.22.453392
Dong Yan Zhang
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
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Jian Wang
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
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Rebecca M. Fleeman
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
2Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
3Center for Neural Engineering, Pennsylvania State University, University Park, PA
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Madison K. Kuhn
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
2Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
3Center for Neural Engineering, Pennsylvania State University, University Park, PA
4Department of Biomedical Engineering, Pennsylvania State University, University Park, PA
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Matthew T. Swulius
6Departments of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
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Elizabeth A. Proctor
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
2Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
3Center for Neural Engineering, Pennsylvania State University, University Park, PA
4Department of Biomedical Engineering, Pennsylvania State University, University Park, PA
5Department of Engineering Science & Mechanics, Pennsylvania State University, University Park, PA
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Nikolay V. Dokholyan
1Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
4Department of Biomedical Engineering, Pennsylvania State University, University Park, PA
6Departments of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA
7Department of Chemistry, Pennsylvania State University, University Park, PA
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  • ORCID record for Nikolay V. Dokholyan
  • For correspondence: dokh@psu.edu
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ABSTRACT

The aggregation of amyloid beta (Aβ) peptide is associated with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils, but also facilitates the maintenance of Aβ oligomers on liposome membranes. We structurally characterize the Aβ oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of Aβ oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aβ oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 22, 2021.
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GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers
Dong Yan Zhang, Jian Wang, Rebecca M. Fleeman, Madison K. Kuhn, Matthew T. Swulius, Elizabeth A. Proctor, Nikolay V. Dokholyan
bioRxiv 2021.07.22.453392; doi: https://doi.org/10.1101/2021.07.22.453392
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GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers
Dong Yan Zhang, Jian Wang, Rebecca M. Fleeman, Madison K. Kuhn, Matthew T. Swulius, Elizabeth A. Proctor, Nikolay V. Dokholyan
bioRxiv 2021.07.22.453392; doi: https://doi.org/10.1101/2021.07.22.453392

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