Advances in a C. elegans model of Alzheimer's disease for drug screening against neurodegeneration

Abstract

Alzheimer’s disease (AD) is the sixth leading cause of death in the United States, yet no treatment effectively prevents, halts or reverses the disease. Progress in developing treatments is hampered by the extensive time required for traditional mouse models of AD to age before displaying histological hallmarks of AD. We set out to test whether a novel transgenic model of AD using the nematode Caenorhabditis elegans may be used to more rapidly determine efficacy of candidate treatments through high throughput screening of behaviors. Our lab previously showed that antagonists for the conserved Sigma-2 receptor (Sig2R) are protective against age- dependent degeneration of cholinergic neurons caused by the human plaque protein, amyloid precursor protein (APP), in this model. To investigate how inhibition of Sig2R protects neurons, we tested whether knockdown of Sig2R via RNA interference prevented decline of two behaviors that depend on these cholinergic neurons. We found that RNAi treatment normalized one of the two behaviors in this AD model suggesting that the antagonists act against the Sig2R in vivo for neuroprotection. The success of this study suggests that this behavioral readout might be used to screen for additional pharmaceutical and genetic modifiers of Sig2R on neurodegeneration. In addition to developing this high throughput behavioral screening, we also built transgene components to generate an improved second generation C. elegans model of AD that conveniently tags the APP protein with mCherry for in vivo fluorescent visualization. Our results set the stage for further drug discovery using our C. elegans models of AD.