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

Abstract

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, 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

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

“…; Jeon et al . ; Sarkar et al . ), resulting in deformed or merged ommatidia instead of the highly organized lattice array in wildtype flies (Ready et al .…”

Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

“…Therefore, many groups have developed Drosophila AD models that directly express Aβ42 in the fly brain for a more direct study of the role of amyloid plaques in AD [32][33][34][35]. Each of the UAS-Aβ42 transgenes produced by these groups have differences in some part of the construct, such as the signal peptide, poly A tail, or the number of Aβ42 copies, which are directly related to the degree of Aβ peptide accumulation and intensity of AD-like phenotypes [36].…”

<i>Nardostachys jatamansi</i> Ethanol Extract Ameliorates Aβ42 Cytotoxicity

“…like phenotypes such as neurodegeneration, increased reactive oxygen species (ROS), neuroinflammation, and learning and memory defects [18][19][20][21] . Using these AD model flies, many reagents with therapeutic potential, as well as genetic modifiers, have been identified 13,[22][23][24][25][26] .…”

“…Measurement of cell death and reactive oxygen species levels For measuring cell death, acridine orange (AO) staining was performed, as previously described 21) . The larval brains were incubated in 1.6 µM AO (Sigma-Aldrich) solution.…”

“…Thus, various AD model flies have been developed, including several human Aβ42-expressing flies [18][19][20][21] , which exhibit AD-…”