A high throughput drug screening paradigm using transgenic Caenorhabditis elegans model of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD), characterized by memory loss and cognitive decline, is one of the diseases with the highest attrition rate in drug development. As with other neurodegenerative diseases, AD manifests on several scales (molecular, cellular and organismal), resulting in an organismal phenotype that is difficult to replicate and exploit for screening in vitro. Development of high-throughput drug screening platforms using invertebrate organisms may therefore facilitate drug discovery in AD, at least for compounds that target mechanisms that can be modelled in invertebrates, such as metabolic defects and mitochondrial toxicity. Here we present a potentially high-throughput screening platform against AD in Caenorhabditis elegans (C. elegans). The system is based on our transgenic AD model strain (GRU102) that expresses a pathogenic human amyloid-beta peptide (Aβ1-42) specifically in neurons and we use this approach to identify Metformin, Lithium and Curcumin as potential “hits”. We find that the ability to rescue the swim-exhaustion phenotype correlates well with lifespan and healthspan improvements in GRU102. Importantly, several other drugs, such as Thioflavin T that have been reported previously to extend lifespan, modify aspects of ageing or for which protective effects in AD model might be suspected did not rescue the swim performance nor lifespan of GRU102. This illustrates the predictive value of the screening assay and confirms that not all compounds targeting ageing are capable of compensating for the toxic effects of Aβ1-42 in GRU102. Together, these findings demonstrate the utility of our screen towards the Aβ-induced defects in GRU102.

Keywords

• Drug screening
• Amyloid beta
• Elegans