Neurotoxic effects induced by the Drosophila amyloid-β peptide suggest a conserved toxic function

The accumulation of amyloid-beta (A beta) into plaques is a hallmark feature of Alzheimer's disease (AD). While amyloid precursor protein (APP)-related proteins are found in most organisms, only V fragments from human APP have been shown to induce amyloid deposits and progressive neurodegeneration. Therefore, it was suggested that neurotoxic effects are a specific property of human A beta. Here we show that A beta fragments derived from the Drosophila orthologue APPL aggregate into intracellular fibrils, amyloid deposits, and cause age-dependent behavioral deficits and neurodegeneration. We also show that APPL can be cleaved by a novel fly beta-secretase-like enzyme. This suggests that A beta-induced neurotoxicity is a conserved function of APP proteins whereby the lack of conservation in the primary sequence indicates that secondary structural aspects determine their pathogenesis. In addition, we found that the behavioral phenotypes precede extracellular amyloid deposit formation, supporting results that intracellular A beta plays a key role in AD. (C) 2008 Elsevier Inc. All rights reserved.