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Phenotypic differences between Drosophila Alzheimer's disease models expressing human A?42 in the developing eye and brain.

ABSTRACT: Drosophila melanogaster expressing amyloid-?42 (A?42) transgenes have been used as models to study Alzheimer's disease. Various A?42 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 A?42 transgenic lines, UAS-A?422X , UAS-A?42BL33770 , UAS-A?4211C39 , and UAS-A?42H29.3 . Among the four transgenic lines, only UAS-A?422X has two copies of the upstream activation sequence-amyloid-?42 (UAS-A?42) transgene, while remaining three have one copy. UAS-A?42BL33770 has the 3' untranslated region of Drosophila ?-tubulin, while the others have that of SV40. UAS-A?4211C39 and UAS-A?42H29.3 have the rat pre-proenkephalin signal peptide, while UAS-A?422X and UAS-A?42BL33770 have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, UAS-A?422X transgene resulted in a strongly reduced and rough eye phenotype, while UAS-A?42BL33770 only showed a strong rough eye phenotype; UAS-A?42H29.3 and UAS-A?4211C39 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-A?422X , followed by UAS-A?42BL33770 , UAS-A?4211C39 , and UAS-A?42H29.3 . 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-A?4211C39 or UAS-A?42H29.3 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: A?42: amyloid-?42; AD: Alzheimer's disease; UAS: upstream activation sequence.

SUBMITTER: Jeon Y

PROVIDER: S-EPMC6138326 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Phenotypic differences between Drosophila Alzheimer's disease models expressing human Aβ42 in the developing eye and brain.

Jeon Youngjae Y Lee Soojin S Shin Myoungchul M Lee Jang Ho JH Suh Yoon Seok YS Hwang Soojin S Yun Hye Sup HS Cho Kyoung Sang KS

Animal cells and systems 20170415 3

Drosophila 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</su ...[more]

PMID: 30460065

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Project description:The ability to express a gene of interest in a spatio-temporal manner using Gal4-UAS system has allowed the use of Drosophila model to study various biological phenomenon. During Drosophila eye development, a synchronous wave of differentiation called Morphogenetic furrow (MF) initiates at the posterior margin resulting in differentiation of retinal neurons. This synchronous differentiation is also observed in the differentiating retina of vertebrates. Since MF is highly dynamic, it can serve as an excellent model to study patterning and differentiation. However, there are not any Gal4 drivers available to observe the gain- of- function or loss- of- function of a gene specifically along the dynamic MF. The decapentaplegic (dpp) gene encodes a secreted protein of the transforming growth factor-beta (TGF-beta) superfamily that expresses at the posterior margin and then moves with the MF. However, unlike the MF associated pattern of dpp gene expression, the targeted dpp-Gal4 driver expression is restricted to the posterior margin of the developing eye disc. We screened GMR lines harboring regulatory regions of dpp fused with Gal4 coding region to identify MF specific enhancer of dpp using a GFP reporter gene. We employed immuno-histochemical approaches to detect gene expression. The rationale was that GFP reporter expression will correspond to the dpp expression domain in the developing eye. We identified two new dpp-Gal4 lines, viz., GMR17E04-Gal4 and GMR18D08-Gal4 that carry sequences from first intron region of dpp gene. GMR17E04-Gal4 drives expression along the MF during development and later in the entire pupal retina whereas GMR18D08-Gal4 drives expression of GFP transgene in the entire developing eye disc, which later drives expression only in the ventral half of the pupal retina. Thus, GMR18D08-Gal4 will serve as a new reagent for targeting gene expression in the ventral half of the pupal retina. We compared misexpression phenotypes of Wg, a negative regulator of eye development, using GMR17E04-Gal4, GMR18D08-Gal4 with existing dpp-Gal4 driver. The eye phenotypes generated by using our newly identified MF specific driver are not similar to the ones generated by existing dpp-Gal4 driver. It suggests that misexpression studies along MF needs revisiting using the new Gal4 drivers generated in our studies.

Dataset Information

Phenotypic differences between Drosophila Alzheimer's disease models expressing human A?42 in the developing eye and brain.

Publications

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

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