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. This article presents a potentially high-throughput screening platform against AD in Caenorhabditis elegans (C. elegans). The system is based on the author’s transgenic AD model strain (GRU102) that expresses a pathogenic human amyloid-beta peptide (Ab1-42) specifically in neurons and this is used to identify Metformin, Lithium and Curcumin as potential “hits”.
The article presents the finding 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 Ab1-42 in GRU102. Together, these findings demonstrate the utility of the authors screen towards the Ab-induced defects in GRU102.
Screening assay workflow. a) Schematic showing workflow for the screening assay design. b) Histogram of frequency distribution showing the number of worms dispensed per well using the TECAN liquid handling system. Data was obtained from two independent trials, n ¼ 96.
The full article can be accessed here.
aNUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore. bScience Division, Yale-NUS College, Singapore. cA*STAR Microscopy Platform, Skin Research Institute of Singapore, Agency for Science Technology and Research, Singapore. dGeriatric Medicine Senior Residency Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore. eSingapore Immunology Network, Agency for Science Technology and Research, Singapore.
