Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau

  1. Sarah L Griner  Is a corresponding author
  2. Paul Seidler
  3. Jeannette Bowler
  4. Kevin A Murray
  5. Tianxiao Peter Yang
  6. Shruti Sahay
  7. Michael R Sawaya
  8. Duilio Cascio
  9. Jose A Rodriguez
  10. Stephan Philipp
  11. Justyna Sosna
  12. Charles G Glabe
  13. Tamir Gonen
  14. David S Eisenberg  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Los Angeles, United States
  2. University of California, Irvine, United States
  3. Janelia Research Campus, Howard Hughes Medical Institute, United States

Abstract

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.

Data availability

Diffraction data have been deposited in PDB under the accession code 6O4JSource Data for Toxicity and Seeding data are provided (Figures 2-7)

The following data sets were generated

Article and author information

Author details

  1. Sarah L Griner

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    sgriner@ucla.edu
    Competing interests
    No competing interests declared.
  2. Paul Seidler

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  3. Jeannette Bowler

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Kevin A Murray

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Tianxiao Peter Yang

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4479-5154
  6. Shruti Sahay

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  7. Michael R Sawaya

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  8. Duilio Cascio

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  9. Jose A Rodriguez

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  10. Stephan Philipp

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
  11. Justyna Sosna

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
  12. Charles G Glabe

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
  13. Tamir Gonen

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9254-4069
  14. David S Eisenberg

    Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    david@mbi.ucla.edu
    Competing interests
    David S Eisenberg, is a SAB member and equity holder in ADRx, Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2432-5419

Funding

National Institutes of Health (R01 AG029430)

  • Sarah L Griner
  • Paul Seidler
  • Jeannette Bowler
  • Kevin A Murray
  • Tianxiao Peter Yang
  • Shruti Sahay
  • Michael R Sawaya
  • Duilio Cascio
  • Jose A Rodriguez
  • David S Eisenberg

Howard Hughes Medical Institute

  • Sarah L Griner
  • Paul Seidler
  • Jeannette Bowler
  • Kevin A Murray
  • Tianxiao Peter Yang
  • Shruti Sahay
  • Michael R Sawaya
  • Duilio Cascio
  • Jose A Rodriguez
  • Tamir Gonen
  • David S Eisenberg

Cure Alzheimer's Fund

  • Stephan Philipp
  • Justyna Sosna
  • Charles G Glabe

National Institutes of Health (R56 AG061847)

  • Paul Seidler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wesley I Sundquist, University of Utah School of Medicine, United States

Version history

  1. Received: March 16, 2019
  2. Accepted: October 4, 2019
  3. Accepted Manuscript published: October 15, 2019 (version 1)
  4. Version of Record published: November 12, 2019 (version 2)

Copyright

© 2019, Griner et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,484
    Page views
  • 954
    Downloads
  • 70
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Sarah L Griner
  2. Paul Seidler
  3. Jeannette Bowler
  4. Kevin A Murray
  5. Tianxiao Peter Yang
  6. Shruti Sahay
  7. Michael R Sawaya
  8. Duilio Cascio
  9. Jose A Rodriguez
  10. Stephan Philipp
  11. Justyna Sosna
  12. Charles G Glabe
  13. Tamir Gonen
  14. David S Eisenberg
(2019)
Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau
eLife 8:e46924.
https://doi.org/10.7554/eLife.46924

Share this article

https://doi.org/10.7554/eLife.46924

Further reading

    1. Biochemistry and Chemical Biology
    Valentin Bohl, Nele Merret Hollmann ... Axel Mogk
    Research Article

    Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during, e.g., food processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL from Listeria monocytogenes that provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Tien M Phan, Young C Kim ... Jeetain Mittal
    Research Article

    The heterochromatin protein 1 (HP1) family is a crucial component of heterochromatin with diverse functions in gene regulation, cell cycle control, and cell differentiation. In humans, there are three paralogs, HP1α, HP1β, and HP1γ, which exhibit remarkable similarities in their domain architecture and sequence properties. Nevertheless, these paralogs display distinct behaviors in liquid-liquid phase separation (LLPS), a process linked to heterochromatin formation. Here, we employ a coarse-grained simulation framework to uncover the sequence features responsible for the observed differences in LLPS. We highlight the significance of the net charge and charge patterning along the sequence in governing paralog LLPS propensities. We also show that both highly conserved folded and less-conserved disordered domains contribute to the observed differences. Furthermore, we explore the potential co-localization of different HP1 paralogs in multicomponent assemblies and the impact of DNA on this process. Importantly, our study reveals that DNA can significantly reshape the stability of a minimal condensate formed by HP1 paralogs due to competitive interactions of HP1α with HP1β and HP1γ versus DNA. In conclusion, our work highlights the physicochemical nature of interactions that govern the distinct phase-separation behaviors of HP1 paralogs and provides a molecular framework for understanding their role in chromatin organization.