[
International Worm Meeting,
2015]
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is the most common cause of dementia in humans. A characteristic feature of AD is the formation of neuronal extracellular senile plaques composed of aggregates of fibrillar amyloid beta (Abeta) peptides. The senile plaques are found in a range amino-truncated and post translationally forms, with Abeta1-42 peptide being the most abundant species. These Abeta peptides have been proposed to contribute to the pathophysiology of the disease; however, there are few tools available to test this hypothesis directly. This project aims to use the model organism, Caenorhabditis elegans, as an in vivo system to study the toxicity associated with these Abeta species. Although C. elegans has been used previously, this is the first report of pan-neuronal transgenic expression of human Abeta1-42. C. elegans strains generated carrying transgenic Abeta1-42 were initially characterized to determine the number of copies of Abeta, from which a number of strains with different level of variation in copy number were identified. A selected strain was subsequently analyzed at the transcript level by quantitative real time PCR (qRT-PCR), which confirmed that that Abeta was being expressed. The effect of neuronal Abeta expression was further characterized using a chemotaxis behavioral assay, which demonstrated minor chemotactic defects in the transgenic C. elegans strains, for all the chemo-attractant compounds tested. Current work is focused on investigating different pan-neuronal gene promoter systems to influence the timing and level of Abeta expression. This work demonstrates the feasibility of expressing human Abeta1-42 in a tractable in vivo system, and in turn, provides a new tool to investigate the in vivo toxicity of Abeta to further enable the study of the molecular and cellular mechanisms underlying AD progression. These strains may also be used in subsequent screens to develop novel therapeutics to treat Alzheimer's disease.