Drosophila expressing Ab as a model for Alzheimer's. A.L. Finelli ¹, P. Grosenstein ², M. Konsolaki ¹. 1) Functional Genomics, Novartis Pharmaceuticals, Summit, NJ; 2) Tox-Pathology, Novartis Pharmaceuticals, East Hanover, NJ.

   Processing of Alzheimers Disease (AD) amyloid precursor protein (APP) gives rise to two forms of amyloid beta (Ab) peptide, the short, less amyloidogenic Ab 40 and the longer, more amyloidogenic Ab 42. The Ab 40 and Ab 42 peptides have been shown to be toxic to neurons, though the mechanisms of toxicity and cell death remain unclear. We have generated a Drosophila model of AD by overexpressing the more amyloidogenic Ab 42 peptide specifically in the Drosophila eye. We show that overexpression of the Ab 42 peptide results in a rough eye phenotype and photoreceptor degeneration, the severity of which is dependent on the peptide dosage. This phenotype is not noticeably suppressed by coexpression of the Drosophila Inhibitor of Apoptosis Proteins (DIAPs) or by p35, suggesting that apoptotic pathways may not be involved in the degeneration. In order to determine the effects of long-term expression of Ab 42 on the eye phenotype, we analyzed eyes of aging flies and observed that the phenotype worsened over the course of four weeks at 29°C. Our Drosophila model thus appears to mimic the progressive and age-associated worsening of the Alzheimer's disease symptoms, an important aspect of the disease. We have also generated flies with eye specific expression of Ab 40, the less amyloidogenic peptide. Analysis of these lines will be reported. Our Ab 42 Drosophila model of AD is being used to screen for mechanisms and molecules which influence Ab aggregation, toxicity and degradation.