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Research Article

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

Dylan Shea, Cheng-Chieh Hsu, Timothy M. Bi, Natasha Paranjapye, View ORCID ProfileMatthew Carter Childers, Joshua Cochran, Colson P. Tomberlin, Libo Wang, Daniel Paris, Jeffrey Zonderman, Gabriele Varani, View ORCID ProfileChristopher D. Link, Mike Mullan, and Valerie Daggett
  1. aDepartment of Molecular Engineering, University of Washington, Seattle, WA 98195;
  2. bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
  3. cDepartment of Chemistry, University of Washington, Seattle, WA 98195;
  4. dDepartment of Integrative Physiology, University of Colorado, Boulder, CO 80309;
  5. eRedshift BioAnalytics, Burlington, MA 01803;
  6. fRoskamp Institute, Sarasota, FL 34243

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PNAS April 30, 2019 116 (18) 8895-8900; first published April 19, 2019; https://doi.org/10.1073/pnas.1820585116
Dylan Shea
aDepartment of Molecular Engineering, University of Washington, Seattle, WA 98195;
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Cheng-Chieh Hsu
bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
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Timothy M. Bi
bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
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Natasha Paranjapye
bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
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Matthew Carter Childers
bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
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Joshua Cochran
cDepartment of Chemistry, University of Washington, Seattle, WA 98195;
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Colson P. Tomberlin
dDepartment of Integrative Physiology, University of Colorado, Boulder, CO 80309;
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Libo Wang
eRedshift BioAnalytics, Burlington, MA 01803;
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Daniel Paris
fRoskamp Institute, Sarasota, FL 34243
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Jeffrey Zonderman
eRedshift BioAnalytics, Burlington, MA 01803;
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Gabriele Varani
cDepartment of Chemistry, University of Washington, Seattle, WA 98195;
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Christopher D. Link
dDepartment of Integrative Physiology, University of Colorado, Boulder, CO 80309;
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Mike Mullan
fRoskamp Institute, Sarasota, FL 34243
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Valerie Daggett
aDepartment of Molecular Engineering, University of Washington, Seattle, WA 98195;
bDepartment of Bioengineering, University of Washington, Seattle, WA 98195;
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  • For correspondence: daggett@uw.edu
  1. Edited by Angela M. Gronenborn, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved March 26, 2019 (received for review December 4, 2018)

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Significance

There have been over 400 clinical trials for Alzheimer’s disease, all targeting the monomeric and/or fibrillar forms of the Aβ peptide to curb amyloid burden; however, it is the toxic soluble oligomers that are correlated with disease progression, not mature amyloid. Here we provide evidence that Aβ soluble oligomers adopt a nonstandard secondary structure: α-sheet. This structure forms early in aggregation and is strongly correlated with toxicity. Furthermore, designed de novo α-sheet peptides target the toxic oligomers, inhibiting aggregation and toxicity in vitro in cell-based assays and in vivo in two different animal models. This work challenges the prevailing dogma and sheds light on potential new approaches to the problem.

Abstract

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

  • α-sheet
  • toxic soluble oligomers
  • Alzheimer’s disease
  • soluble oligomer binding assay
  • amyloid beta

Footnotes

  • ↵1To whom correspondence should be addressed. Email: daggett{at}uw.edu.
  • Author contributions: D.S., J.Z., G.V., C.D.L., M.M., and V.D. designed research; D.S., C.-C.H., T.M.B., N.P., M.C.C., J.C., C.P.T., L.W., and D.P. performed research; D.S., C.-C.H., T.M.B., N.P., M.C.C., C.P.T., L.W., D.P., C.D.L., M.M., and V.D. analyzed data; and D.S., D.P., G.V., C.D.L., M.M., and V.D. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The NMR data reported in this paper have been deposited in the BioMagResBank, www.bmrb.wisc.edu (accession no. 27873).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820585116/-/DCSupplemental.

Published under the PNAS license.

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α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease
Dylan Shea, Cheng-Chieh Hsu, Timothy M. Bi, Natasha Paranjapye, Matthew Carter Childers, Joshua Cochran, Colson P. Tomberlin, Libo Wang, Daniel Paris, Jeffrey Zonderman, Gabriele Varani, Christopher D. Link, Mike Mullan, Valerie Daggett
Proceedings of the National Academy of Sciences Apr 2019, 116 (18) 8895-8900; DOI: 10.1073/pnas.1820585116

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α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease
Dylan Shea, Cheng-Chieh Hsu, Timothy M. Bi, Natasha Paranjapye, Matthew Carter Childers, Joshua Cochran, Colson P. Tomberlin, Libo Wang, Daniel Paris, Jeffrey Zonderman, Gabriele Varani, Christopher D. Link, Mike Mullan, Valerie Daggett
Proceedings of the National Academy of Sciences Apr 2019, 116 (18) 8895-8900; DOI: 10.1073/pnas.1820585116
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Proceedings of the National Academy of Sciences: 116 (18)
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  • Article
    • Abstract
    • Aβ Forms Toxic Oligomers During the Lag Phase of Aggregation
    • Toxic Oligomers Contain α-Sheet Structure, Not β-Sheet Structure
    • De Novo α-Sheet Peptides Specifically Bind Toxic Oligomers
    • α-Sheet Peptides Inhibit Aβ Aggregation and Cytotoxicity
    • α-Sheet Designs Decrease Toxic Oligomers in AD Mouse Model
    • α-Sheet Peptides Inhibit Aβ-Induced Paralysis in AD C. elegans Model
    • Conclusions
    • Methods
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    • References
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