Utility of an improved model of amyloid-beta (Aβ_1-42) toxicity in Caenorhabditis elegans for drug screening for Alzheimer’s disease

摘要

Background The definitive indicator of Alzheimer’s disease (AD) pathology is the profuse accumulation of amyloid-? (A?) 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 A? 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 A?1-42. This strain differs from existing A? models that predominantly express amino-truncated A?3-42. The A?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 A?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 A?-induced toxicity in C. elegans. Conclusion This C. elegans model of full length A?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 A?.