Phenotypic differences between<i>Drosophila</i>Alzheimer’s disease models expressing human<i>Aβ42</i>in the developing eye and brain

Abstract

<i>Drosophila melanogaster</i> expressing amyloid-β42 (<i>Aβ42</i>) transgenes have been used as models to study Alzheimer's disease. Various <i>Aβ42</i> transgenes with different structures induce different phenotypes, which make it difficult to compare data among studies which use different transgenic lines. In this study, we compared the phenotypes of four frequently used <i>Aβ42</i> transgenic lines, <i>UAS-Aβ42^2X</i> , <i>UAS-Aβ42^BL33770</i> , <i>UAS-Aβ42^11C39</i> , and <i>UAS-Aβ42^H29.3</i> . Among the four transgenic lines, only <i>UAS-Aβ42^2X</i> has two copies of the upstream activation sequence-amyloid-β42 (<i>UAS-Aβ42</i>) transgene, while remaining three have one copy. <i>UAS-Aβ42^BL33770</i> has the 3' untranslated region of <i>Drosophila α-tubulin</i>, while the others have that of SV40. <i>UAS-Aβ42^11C39</i> and <i>UAS-Aβ42^H29.3</i> have the rat pre-proenkephalin signal peptide, while <i>UAS-Aβ42^2X</i> and <i>UAS-Aβ42^BL33770</i> have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, <i>UAS-Aβ42^2X</i> transgene resulted in a strongly reduced and rough eye phenotype, while <i>UAS-Aβ42^BL33770</i> only showed a strong rough eye phenotype; <i>UAS-Aβ42^H29.3</i> and <i>UAS-Aβ42^11C39</i> had mild rough eyes. The levels of cell death and reactive oxygen species (ROS) in the eye imaginal discs were consistently the highest in <i>UAS-Aβ42^2X</i> , followed by <i>UAS-Aβ42^BL33770</i> , <i>UAS-Aβ42^11C39</i> , and <i>UAS-Aβ42^H29.3</i> . Surprisingly, the reduction in survival during the development of these lines did not correlate with cell death or ROS levels. The flies which expressed <i>UAS-Aβ42^11C39</i> or <i>UAS-Aβ42^H29.3</i> experienced greatly reduced survival rates, although low levels of ROS or cell death were detected. Collectively, our results demonstrated that different <i>Drosophila</i> AD models show different phenotypic severity, and suggested that different transgenes may have different modes of cytotoxicity. <b>Abbreviations:</b> Aβ42: amyloid-β42; AD: Alzheimer's disease; UAS: upstream activation sequence.