A model for studying Alzheimer's Aβ42-induced toxicity in Drosophila melanogaster

Alzheimer's disease is a neurological disorder resulting in the degeneration and death of brain neurons controlling memory, cognition and behavior. Although overproduction of A peptides is widely considered a causative event in the disease, the mechanisms by which Abeta peptides cause neurodegeneration and the processes of Abeta clearance and degradation remain unclear. To address these issues, we have expressed the Abeta peptides in Drosophila melanogaster. We show that overexpression of Abeta(42) peptides in the nervous system results in phenotypes associated with neuronal degeneration in a dose- and age-dependent manner. We further show that a mutation in a Drosophila neprilysin gene suppresses the Abeta(42) phenotypes by lowering the levels of the Abeta(42) peptide, supporting the role of neprilysin in the catabolism of Abeta peptides in vivo. We propose that our Drosophila model is suitable for the study and elucidation of Abeta metabolism and toxicity at the genetic level. (C) 2004 Elsevier Inc. All rights reserved.