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
No Available References
- Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y. 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.