Removal of extracellular human amyloid beta aggregates by extracellular proteases in C. elegans

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Abstract

The amyloid-beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ_1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in-vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.

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All source data, raw data, screening hits, plasmid sequences, and statistical information are provided in DataSourceFiles and in Supplementary Files 1-4.

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Elisabeth Jongsma

Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland

Competing interests
The authors declare that no competing interests exist.
Anita Goyala

Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9196-2915
José Maria Mateos

Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3675-6198
Collin Yvès Ewald

Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland

For correspondence
collin-ewald@ethz.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1166-4171

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_163898)

Collin Yvès Ewald

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (190072)

Elisabeth Jongsma
Anita Goyala
Collin Yvès Ewald

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

Copyright

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.