A transgenic Drosophila model of AD shows learning deficits, reduced lifespan, amyloid buildup, and neurodegeneration in response to expression of human Aβ42, as described in PNAS Early Edition. The human Aβ40 fragment produced a similar learning deficit without obvious pathology.

What does a fly have to forget, one might well ask? Granted, not the names of its grandchildren or the shopping list, but it can forget the simplest form of aversive Pavlovian conditioning. Senior author Yi Zhong and colleagues at Cold Spring Harbor Laboratory in New York, as well as at Nation Tsing Hua University in Hsinchu, Taiwan, and Novartis Pharamceuticals in Summit, New Jersey, paired certain odors with electric shocks, and tested the flies on their subsequent ability to avoid the "shocking" odor. Both Aβ40 and -42 expression produced deficits in flies by age 6 to 7 days, and these deficits grew by age 14 to 15 days. It appears, however, that greater amounts of Aβ40 expression were required to produce the learning deficits. The researchers were unable to test whether the deficits continued to grow after this age, because the Aβ42 flies, (though not the Aβ40 flies) showed a concurrent decline in locomotion.

In normal flies—and in Aβ40 flies—old-age mortality begins with a steep increase just after 60 days, and most flies are dead by 80 days of age. The Aβ42 transgenic flies began to die in large numbers after 40 days, with most dead by about 60 days.

Neurodegeneration detected by confocal microscopy began in a small way around age 30 in the Aβ42 flies, and became significant 15 days later. At 48 days, these transgenics had significant amyloid deposits. Neither neurodegeneration nor amyloid buildup was evident in Aβ40 flies even in very old age. Neither transgenic fly showed any evidence of abnormal tau buildup.

"It is remarkable to note that in an organism with a life span of 2–3 months, accumulation of Aβ42 induces the sequential progression of pathological symptoms resembling those in mouse AD models and AD patients. Intriguingly, the onset of learning defects by Aβ42 occurs much earlier than that of degeneration in the flies, similar to that observed in mouse AD models and AD patients," write the authors.

The results might be construed to support the notion that the mechanisms of AD learning and memory deficits are not directly associated with neurodegeneration, given that Aβ40 produced learning deficits without the neurodegeneration.—Hakon Heimer

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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.

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Further Reading

Primary Papers

  1. . 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.