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Mol Neurodegener. 2012 Nov 21;7:57. doi: 10.1186/1750-1326-7-57.

Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease.

Author information

1
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3010, Australia. gmccoll@unimelb.edu.au

Abstract

BACKGROUND:

The definitive indicator of Alzheimer's disease (AD) pathology is the profuse accumulation of amyloid-ß (Aß) within the brain. Various in vitro and cell-based models have been proposed for high throughput drug screening for potential therapeutic benefit in diseases of protein misfolding. Caenorhabditis elegans offers a convenient in vivo system for examination of Aß accumulation and toxicity in a complex multicellular organism. Ease of culturing and a short life cycle make this animal model well suited to rapid screening of candidate compounds.

RESULTS:

We have generated a new transgenic strain of C. elegans that expresses full length Aß₁₋₄₂. This strain differs from existing Aß models that predominantly express amino-truncated Aß₃₋₄₂. The Aß₁₋₄₂ is expressed in body wall muscle cells, where it oligomerizes, aggregates and results in severe, and fully penetrant, age progressive-paralysis. The in vivo accumulation of Aß₁₋₄₂ also stains positive for amyloid dyes, consistent with in vivo fibril formation. The utility of this model for identification of potential protective compounds was examined using the investigational Alzheimer's therapeutic PBT2, shown to be neuroprotective in mouse models of AD and significantly improve cognition in AD patients. We observed that treatment with PBT2 provided rapid and significant protection against the Aß-induced toxicity in C. elegans.

CONCLUSION:

This C. elegans model of full length Aß₁₋₄₂ expression can now be adopted for use in screens to rapidly identify and assist in development of potential therapeutics and to study underlying toxic mechanism(s) of Aß.

PMID:
23171715
PMCID:
PMC3519830
DOI:
10.1186/1750-1326-7-57
[Indexed for MEDLINE]
Free PMC Article

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