Levels of Amyloid Beta () Expression in the 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 () peptides, with the peptide being the most abundant species. These 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 peptide expression level and disease. We have generated a panel of transgenic strains expressing the human peptide under the control of promoter regions of two pan-neuronal expressed genes, and . 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 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 were strongly positively correlated with expression level. The pan-neuronal expression of varying levels of human in a nematode model provides a new tool to investigate the in vivo toxicity of neuronal expression and the molecular and cellular mechanisms underlying AD progression in the absence of endogenous peptides. More importantly, it allows direct quantitative testing of the dose-response relationship between neuronal 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.