Alzheimer's Research Takes Wing
You have probably seen them buzzing around ripe peaches on the kitchen counter in summertime, or perhaps in biology class, where you noted the red-eyed versus the white-eyed version. Beyond these casual encounters, decades of work by thousands of scientists have made Drosophila melanogaster, commonly called the fruit fly, a crown jewel of biology and genetics research.
We differ obviously from the fly in many ways, but because we have much in common with it (e.g. thousands of very similar genes, a nervous system, and an ability to learn and remember), studies of the fly have revealed a great deal of information about human biology and disease. CSHL neurobiologist Yi Zhong is now using the power of Drosophila research to model and unravel the causes of Alzheimer's disease in humans.
"Believe it or not, the same proteins implicated in human Alzheimer's disease are present in the fruit fly brain. So we have arranged things to be able to study Alzheimer's disease in the fly. This should give us valuable clues about how the disease develops in humans and what might be done to treat Alzheimer's. We started this project only one year ago, and we're already getting some very encouraging results," says Yi.
 Alzheimer's disease is a progressive, fatal, neurodegenerative disorder that affects the nerve cells of the brain. It is the most common form of dememtia in humans. No cure or effective treatment is available, and the root causes of the disease are unclear. By the year 2050, as many as 20 million Americans may be afflicted with the disease. Alzheimer's symptoms include memory loss, disorientation, confusion, and difficulty with reasoned thought (so-called cognitive symptoms) and may also include agitation, anxiety, delusions, depression, insomnia, or wandering (behavioral symptoms).
The key question is what are the steps in Alzheimer's disease progression that, if inhibited by treatment, would slow or prevent the disease? For his first set of experiments, Yi decided to focus on a protein strongly implicated in the pathology of Alheimer's disease called amyloid precursor protein or APP. APP can be cleaved into a shorter, B-amyloid ("beta-amyloid") protein called AB42 ("A-beta-forty-two"). AB42 is a major component of senile "plaques" which are one form of brain lesion associated with Alzheimer's disease in humans.
To create a fruit fly model of Alzheimer's, Yi and his collegues modified a human gene that encodes amyloid precursor protein so that the AB42 fragment would be produced and secreted in the brains of flies. Then, to determine the affect of such B-amyloid production on brain function, Yi used a method pioneered by his CSHL colleague Tim Tully which measures the ability of flies to form and recall memories.
Tim's Method involves a learning phase, during which flies are trained to associate a specific color with a mild electric shock, followed some time later by a memory test, which measures the ability of the flies to avoid the odor they were trained to avoid.
Through their research over the past several years, Tim and his colleagues have established that normal, healthy flies easily learn to avoid a specific odor. Moreover, Time has shown that flies can form a long-term memory of what they learn, avoiding the odor long after they were trained to. He and his colleagues have identified several genes that are required for learning and memory in flies. Remarkably, many of these genes have similar counterparts in humans.
Yi discovered several important things when he produced the human Alzheimer's-associated AB42 protein in the fruit fly brain. As in young humans who eventually develop Alzheimer's, learning and memory were normal in young, 2 to 3-day-old flies (the typical life span of fruit flies is four weeks). However, after one week, the flies began to display learning defects, at a time when "plaques" were scarcely detectable when Yi examinedfly brains under the microscope.
After two weeks, Yi observed more severe learning defects in the flies, and he began to see abundant plaques reminiscent of human Alzheimer's disease in the fly brains (see figure, page 13). At three weeks of age, flies producing AB42 protein began to display "motor defects" (an inability to move normally), which prevented Yi from testing their learning defects. Flies this age displayed a large amount of brain nerve cell death (neurodegeneration), which, like plaque formation, is a hallmark of human Alzheimer's disease.
Yi's study is significant in many ways. Owing to the learning defects, plaque formation, and nerve cell death it revealed as flies age, the study has established that the fruit fly is indeed a useful model system with which to study human Alzheimer's disease. The study also showed tha the production of AB42 protein alone is sufficient to trigger Alzheimer's-related processes. Such processes can be studied in the fly much more quickly and with fewer resources and lower cost than is required for similar studies in mouse models.
Given the power of fruit fly genetics to reveal the molecular components and intricate pathways involved in complex biological processes, Yi and his colleagues are in a good position to use their Drosophila model of Alzheimer's to uncover much new information about the disease. For example, Yi's "Alzheimer's Flies" can be used to test new theories about how the disease progresses, to identify new gene or protein targets for treating the disease, or to rapidly screen large numbers of drugs for those that might slow or prevent plaque formation or nerve cell death in the brain. Research using mouse models of Alzheimer's are still essential, but the fly may now lead the way for some studies of this devastating illness.
---Peter W. Sherwood.
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