. Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6623-8. PubMed.

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  1. The generation and phenotyping of Aβ40- and Aβ42-specific Drosophila transgenic lines make a valuable contribution to identifying the differences between these two peptides. By showing that both Aβ40 and Aβ42 form oligomers, but that only Aβ42 is deposited into insoluble fractions and inclusion bodies, this study provides further evidence that Aβ42 has more amyloidogenic properties. However, this result is not that surprising, given that enhanced fibrillogenesis of the longer species has been reported many times. What is possibly surprising is that both forms, including the less fibrillogenic and less easily deposited Aβ40, cause a subtle learning disorder. Again, the Aβ42 flies showed a greater deficit than the Aβ40 flies, demonstrating that even if the two peptides are not qualitatively different, they do behave in a quantitatively different manner. Two additional phenotypes—an age-related loss of motor function and shortened lifespan—are measurable only in the Aβ fly lines. Although Iijima and colleagues plausibly argue that this means there are different mechanisms of action of these two species, one might also suggest that this is still a qualitative difference but with a threshold effect for expression. A thoughtful experiment would be to use multiple levels of expression (perhaps with an inducible promoter) to see if there are doses at which Aβ40 becomes more Aβ42-like, or whether these differences are absolute. Finally, of course, one would like to see a replication of this phenotype in a vertebrate system. The lack of tau pathology in this model compared to the prominent pathology in the human disease leads to the question of whether the pathways are truly identical. There are systems by which one might selectively deliver each of these peptides in mammalian cell systems (Lewis et al., 2001), suggesting that one might be able to try to replicate these findings in higher animals.

    References:

    . Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides. Biochim Biophys Acta. 2001 Jul 27;1537(1):58-62. PubMed.

    View all comments by Mark Cookson

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