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

Neurobiology of Disease

卷:33

Thomas Proctor¹  Doris Kretzschmar¹  Katia Carmine-Simmen¹  Jakob Tschäpe¹  Roland Strauss²  Tilman Triphan²  Burkhard Poeck² 

[1] Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA;

[2] Lehrstuhl für Genetik und Neurobiologie, Universität Würzburg, 97074 Würzburg, Germany;

关键词: APP;    APPL;    Drosophila;    Amyloid;    Neurodegeneration;    β-secretase;   

DOI  :  

来源: DOAJ

【 摘 要 】

The accumulation of amyloid-β (Aβ) into plaques is a hallmark feature of Alzheimer's disease (AD). While amyloid precursor protein (APP)-related proteins are found in most organisms, only Aβ 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 Aβ. Here we show that Aβ 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 β-secretase-like enzyme. This suggests that Aβ-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 Aβ plays a key role in AD.

【 授权许可】

Unknown