Abstract 1526 Extracellular Aggregation of Ab Plaques in Alzheimer's Disease

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of protein aggregates called Ab plaques. The main component of these aggregates is a small peptide that is derived from the APP protein, called Ab. APP is embedded within the cell membrane and is typically cleaved to produce a 40 amino acid fragment called Ab40. However, in AD APP is cleaved to produce a larger fragment of 42 amino acids (Ab42) that aggregates in the extracellular space. Aggregation of mutant AB42s has been linked to the onset of Alzheimer's disease. In this experiment, several AB42 mutants will be expressed in specific locations within the flies to examine the effects on health span and longevity. Each of the AB42 mutants have different structural conformations which may lead to various levels of aggregation. p38 MAPK (p38K) activation has been associated with AD, and we have found that p38K regulates aging and protein homeostasis in the fruit fly, Drosophila melanogaster. Therefore, we hypothesize that p38K promotes the degradation of Ab40 and that this process is disrupted in AD. We have found that expression of AB42 in neurons of the flies leads to premature death, whereas the expression of the AB40 control did not result in any significant changes in lifespan. This research was funded by the National Institute of Aging and the Oregon State University LIFE Scholars Program.