Fossgreen A, Brückner B, Czech C, Masters C L, Beyreuther K, Paro R
Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13703-8. doi: 10.1073/pnas.95.23.13703.
The importance of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease (AD) became apparent through the identification of distinct mutations in the APP gene, causing early onset familial AD with the accumulation of a 4-kDa peptide fragment (betaA4) in amyloid plaques and vascular deposits. However, the physiological role of APP is still unclear. In this work, Drosophila melanogaster is used as a model system to analyze the function of APP by expressing wild-type and various mutant forms of human APP in fly tissue culture cells as well as in transgenic fly lines. After expression of full-length APP forms, secretion of APP but not of betaA4 was observed in both systems. By using SPA4CT, a short APP form in which the signal peptide was fused directly to the betaA4 region, transmembrane domain, and cytoplasmic tail, we observed betaA4 release in flies and fly-tissue culture cells. Consequently, we showed a gamma-secretase activity in flies. Interestingly, transgenic flies expressing full-length forms of APP have a blistered-wing phenotype. As the wing is composed of interacting dorsal and ventral epithelial cell layers, this phenotype suggests that human APP expression interferes with cell adhesion/signaling pathways in Drosophila, independently of betaA4 generation.
淀粉样前体蛋白（APP）在阿尔茨海默病（AD）发病机制中的重要性，通过APP基因中不同突变的鉴定得以显现，这些突变导致早发性家族性AD，伴有4 kDa肽片段（βA4）在淀粉样斑块和血管沉积物中的积累。然而，APP的生理功能仍不清楚。在这项研究中，黑腹果蝇被用作模型系统，通过在果蝇组织培养细胞以及转基因果蝇品系中表达野生型和各种突变形式的人类APP来分析APP的功能。在全长APP形式表达后，在两个系统中均观察到APP的分泌，但未观察到βA4的分泌。通过使用SPA4CT（一种信号肽直接与βA4区域、跨膜结构域和细胞质尾巴融合的短APP形式），我们在果蝇和果蝇组织培养细胞中观察到了βA4的释放。因此，我们在果蝇中显示出γ-分泌酶活性。有趣的是，表达全长APP形式的转基因果蝇具有翅疱表型。由于翅膀由相互作用的背侧和腹侧上皮细胞层组成，这种表型表明人类APP的表达干扰了果蝇中的细胞粘附/信号通路，与βA4的产生无关。
