Levels of Amyloid Beta (Aβ) Expression in the Caenorhabditis elegans Neurons Influence the Onset and Severity of Neuronally Mediated Phenotypes

A characteristic feature of Alzheimer's disease (AD) is the formation of neuronal extracellular senile plaques composed of aggregates of fibrillar amyloid β (<i>Aβ</i>) peptides, with the <i>Aβ1-42</i> peptide being the most abundant species. These <i>Aβ</i> peptides have been proposed to contribute to the pathophysiology of the disease; however, there are few tools available to test this hypothesis directly. In particular, there are no data that establish a dose-response relationship between <i>Aβ</i> peptide expression level and disease. We have generated a panel of transgenic <i>Caenorhabditis elegans</i> strains expressing the human <i>Aβ1-42</i> peptide under the control of promoter regions of two pan-neuronal expressed genes, <i>snb-1</i> and <i>rgef-1</i>. Phenotypic data show strong age-related defects in motility, subtle changes in chemotaxis, reduced median and maximum lifespan, changes in health span indicators, and impaired learning. The <i>Aβ1-42</i> expression level of these strains differed as a function of promoter identity and transgene copy number, and the timing and severity of phenotypes mediated by <i>Aβ1-42</i> were strongly positively correlated with expression level. The pan-neuronal expression of varying levels of human <i>Aβ1-42</i> in a nematode model provides a new tool to investigate the in vivo toxicity of neuronal <i>Aβ</i> expression and the molecular and cellular mechanisms underlying AD progression in the absence of endogenous <i>Aβ</i> peptides. More importantly, it allows direct quantitative testing of the dose-response relationship between neuronal <i>Aβ</i> peptide expression and disease for the first time. These strains may also be used to develop screens for novel therapeutics to treat Alzheimer's disease.