Application of optogenetic Amyloid-β distinguishes between metabolic and physical damage in neurodegeneration

Abstract

The brains of Alzheimer's Disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer's Disease is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of Alzheimer's Disease. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chu Hsien Lim

    Science Division, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6691-8277
  2. Prameet Kaur

    Science Division, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Emelyne Teo

    NUS Graduate School for Integrative Sciences and Engineering, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5050-4109
  4. Vanessa Yuk Man Lam

    Science Division, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Fangchen Zhu

    Science Division, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Caroline Kibat

    Science, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Jan Gruber

    Science Division, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3329-3789
  8. Ajay S Mathuru

    Science, Yale-NUS College, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4591-5274
  9. Nicholas S Tolwinski

    Science Division, Yale-NUS College, Singapore, Singapore
    For correspondence
    nicholas.tolwinski@yale-nus.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8507-2737

Funding

Ministry of Education Singapore (IG17-LR001)

  • Nicholas S Tolwinski

Ministry of Education Singapore (IG18-LR001)

  • Nicholas S Tolwinski

Ministry of Education Singapore (IG17-BS101)

  • Jan Gruber

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

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Publication history

  1. Received: October 9, 2019
  2. Accepted: March 18, 2020
  3. Accepted Manuscript published: March 31, 2020 (version 1)
  4. Version of Record published: April 9, 2020 (version 2)

Copyright

© 2020, Lim 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.

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  1. Chu Hsien Lim
  2. Prameet Kaur
  3. Emelyne Teo
  4. Vanessa Yuk Man Lam
  5. Fangchen Zhu
  6. Caroline Kibat
  7. Jan Gruber
  8. Ajay S Mathuru
  9. Nicholas S Tolwinski
(2020)
Application of optogenetic Amyloid-β distinguishes between metabolic and physical damage in neurodegeneration
eLife 9:e52589.
https://doi.org/10.7554/eLife.52589
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