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

Molecular Neurodegeneration

Robert A Cherny³  Ashley I Bush³  Kevin J Barnham²  Colin L Masters³  Timothy M Ryan³  Christopher D Link¹  Christine M Roberts¹  Vijaya B Kenche²  Tara L Pukala⁴  Blaine R Roberts³  Gawain McColl³ 

[1] Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA;Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia;The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, 3010, Australia;University of Adelaide, Adelaide, South Australia, Australia

关键词: PBT2 and drug screen;    8-hydroxyquinoline;    Caenorhabditis elegans;    Alzheimer’s disease;    Amyloid beta peptide;   

Others  :  863299
DOI  :  10.1186/1750-1326-7-57

 received in 2012-04-16, accepted in 2012-11-15,  发布年份 2012

【 摘 要 】

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 Aß_1-42. This strain differs from existing Aß models that predominantly express amino-truncated Aß_3-42. The Aß_1-42 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 Aß_1-42 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 Aß_1-42 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.

【 授权许可】

   
2012 McColl et al.; licensee BioMed Central Ltd.

【 图 表 】

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