1. Developmental Biology
  2. Neuroscience
Download icon

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

Tools and Resources
  • Cited 2
  • Views 2,365
  • Annotations
Cite this article as: eLife 2020;9:e52589 doi: 10.7554/eLife.52589

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.

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.

Metrics

  • 2,365
    Page views
  • 349
    Downloads
  • 2
    Citations

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

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)

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

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

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    David Melamed, Daniel Kalderon
    Research Article Updated

    Many adult stem cell communities are maintained by population asymmetry, where stochastic behaviors of multiple individual cells collectively result in a balance between stem cell division and differentiation. We investigated how this is achieved for Drosophila Follicle Stem Cells (FSCs) by spatially-restricted niche signals. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. We show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC domain, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. Wnt pathway activity declines from the anterior, promotes anterior FSC locations and EC production, and opposes FC production. The pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs and FCs at either end of opposing signaling gradients, and impose a pattern of proliferation that matches derivative production.

    1. Developmental Biology
    2. Neuroscience
    André Ferreira Castro et al.
    Research Article

    Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.