Abstract
ABSTRACTDrosophila melanogaster expressing amyloid-β42 (Aβ42) transgenes have been used as models to study Alzheimer’s disease. Various Aβ42 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 Aβ42 transgenic lines, UAS-Aβ422X, UAS-Aβ42BL33770, UAS-Aβ4211C39, and UAS-Aβ42H29.3. Among the four transgenic lines, only UAS-Aβ422X has two copies of the upstream activation sequence-amyloid-β42 (UAS-Aβ42) transgene, while remaining three have one copy. UAS-Aβ42BL33770 has the 3′ untranslated region of Drosophila α-tubulin, while the others have that of SV40. UAS-Aβ4211C39 and UAS-Aβ42H29.3 have the rat pre-proenkephalin signal peptide, while UAS-Aβ422X and UAS-Aβ42BL33770 have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, UAS-Aβ422X transgene resulted in a strongly reduced and rough eye phenotype, while UAS-Aβ42BL33770 only showed a strong rough eye phenotype; UAS-Aβ42H29.3 and UAS-Aβ4211C39 had mild rough eyes. The levels of cell death and reactive oxygen species (ROS) in the eye imaginal discs were consistently the highest in UAS-Aβ422X, followed by UAS-Aβ42BL33770, UAS-Aβ4211C39, and UAS-Aβ42H29.3. Surprisingly, the reduction in survival during the development of these lines did not correlate with cell death or ROS levels. The flies which expressed UAS-Aβ4211C39 or UAS-Aβ42H29.3 experienced greatly reduced survival rates, although low levels of ROS or cell death were detected. Collectively, our results demonstrated that different Drosophila AD models show different phenotypic severity, and suggested that different transgenes may have different modes of cytotoxicity.Abbreviations: Aβ42: amyloid-β42; AD: Alzheimer’s disease; UAS: upstream activation sequence
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by amyloid plaques, neurofibrillary tangles, and loss of neurons (Mattson 2004)
The amyloid hypothesis states that most of AD pathologies are caused by deposition of amyloid-β42 (Aβ42) peptide, which is generated by proteolytic processing of the amyloid precursor protein (Hardy & Higgins 1992)
The expression level of Aβ42 protein by the upstream activation sequence (UAS)-Aβ4211C39 line was higher than that of UASAβ42H29.3 (Figure 2), despite having Aβ42 transgenes with the same structure (Figure 1), which suggested that their difference might be caused by a position effect
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by amyloid plaques, neurofibrillary tangles, and loss of neurons (Mattson 2004). We compared the phenotypes of four frequently used Aβ42 transgenic lines, UAS-Aβ422X, UAS-Aβ42BL33770, UAS-Aβ4211C39, and UAS-Aβ42H29.3. The flies which expressed UAS-Aβ4211C39 or UAS-Aβ42H29.3 experienced greatly reduced survival rates, low levels of ROS or cell death were detected.
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