HEALTH / ALZHEIMER’S DISEASE : Researchers Produce Mice With Key Feature of Illness
Three U.S. research groups, including two in California, report they have independently made a major advance toward understanding the cause of Alzheimer’s disease, the degenerative neurological disorder that is the fourth leading cause of death in the United States.
Each of the three groups has used genetic engineering techniques to produce mice whose brains develop protein deposits, or plaques, the major physical feature of Alzheimer’s. Many scientists believe plaques are a cause of the disease.
This first animal model of the disease could lead to development of drugs that can block plaque formation and thereby retard progression of Alzheimer’s.
The developments, reported this week in the journals Nature and Science, are very important because they will for the first time allow researchers to study the biochemical basis of Alzheimer’s, according to neurologist Zevan Khachaturian of the National Institute on Aging.
“This is going to give us a laboratory to study how (the protein) gets processed in the mammalian brain--what makes (the disease) worse, what makes it better, how you can stop it,” said Creighton Phelps of the Alzheimer’s Assn. “Those are the kinds of things you can’t do in humans. It’s a very important research project, and it can only be done in animals.”
Alzheimer’s disease is characterized by memory loss, disorientation, depression and deterioration of bodily functions. According to the National Institute on Aging, it affects about 4 million Americans and causes 100,000 deaths annually.
There is no effective therapy for Alzheimer’s, but a Food and Drug Administration advisory panel on Monday recommended that a memory-enhancement drug called THA be given wider distribution, even though clinical trials have produced equivocal results.
The most noticeable biological sign of Alzheimer’s is the presence of the protein plaques in the regions of the brain that control memory and learning, most notably the hippocampus and the cortex. In humans, these plaques are detectable only by an autopsy after death. The only other animals in which the plaques form naturally are chimpanzees, and they are too long-lived and expensive for routine study.
Neurologists have been intensely debating whether the accumulation of plaques causes the symptoms of Alzheimer’s “or whether it is something that is inconsequential and just a byproduct of what we should be studying,” said molecular biologist Barbara Cordell of California Biotechnology Inc. in Mountain View.
The development of the mouse models for Alzheimer’s should provide researchers the tool to end the debate. One model was developed by molecular biologist Dana Wirak and his colleagues at the Miles Research Center in West Haven, Conn., and is being reported in Science today. Cordell and her colleagues have developed a similar model that was reported in Nature on Thursday. Neurologist Rachel Neve and her associates at UC Irvine have developed a third model that has not yet been published.
In each case, the researchers took the gene that serves as a blueprint for the beta-amyloid protein that forms the plaques--or, in one case, for a precursor molecule--and inserted it into fertilized mouse eggs. In those mice in which the added gene was successfully incorporated into the animals’ own genetic library, plaques began accumulating in their brains before they reached the age of 1 year, the equivalent of age 40 in humans.
None of the research groups have begun looking for behavioral changes in the animals yet. They want to wait until the mice are older so any such changes will be more readily observable.
If such changes are seen, according to the Phelps of the Alzheimer’s Assn., that will be a clear sign that the plaques cause the disorder. If the changes are not observed, researchers will have to reformulate their ideas about what causes the disease.
