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.