Researchers have used genetic engineering techniques to produce mice that show all the symptoms of Alzheimer's disease, an advance that should speed up the search for new therapies for the degenerative disorder, which is the fourth leading cause of death in the United States.
Previously, scientists had produced mice that developed protein deposits, or plaques, in their brains, the most important physical feature of Alzheimer's, but they had no other obvious signs of the disorder.
The new mice, described in a report today in the British journal Nature, not only develop the plaques, but also suffer the death of large numbers of brain cells and show behavioral impairments characteristic of Alzheimer's in humans.
"This development accelerates dramatically the opportunity to learn more about what causes Alzheimer's disease and to find a biological indicator which could eliminate the clinical guesswork in diagnosis," said gerontologist Robert Butler of the Mt. Sinai Medical Center in New York City.
The new report represents "a significant step forward," said Creighton Phelps, vice president for scientific and medical affairs of the Alzheimer's Assn. "It will allow us to test potential drug treatments on animals rather than humans. Using an animal model, we would be able to screen many therapeutic agents in a relatively short period of time, something you couldn't do on human patients."
Production of the mice "brings us a step closer to our major goal: to fundamentally alter the course of the disease by the end of the decade," said gerontologist Gene Cohen, acting director of the National Institute on Aging. "If we can delay the onset of (Alzheimer's) by five years, we could cut the incidence of the disease by 50%."
Alzheimer's disease is characterized by memory loss, disorientation, depression and deterioration of bodily functions. It affects about 4 million Americans, most over the age of 65, and causes 100,000 deaths annually. No effective therapy for Alzheimer's exists, but the U.S. Food and Drug Administration has given limited approval for use of a memory-enhancing drug called tacrine or THA.
The most noticeable biological sign of Alzheimer's is the presence of protein plaques in the regions of the brain that control memory and learning, most notably the cortex and the hippocampus. 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.
In July, three research groups independently reported that they had used genetic engineering techniques to insert in mice the gene for a protein called beta-amyloid, the primary component of Alzheimer's plaques. The mice developed the plaques as they aged, but none of the research groups have yet reported the development of any adverse effects caused by the plaques.
In the new study, molecular biologists Jon W. Gordon of Mt. Sinai, Shigeki Kawabata of Yamanouchi Pharmaceutical Co. Ltd. of Tokyo and Gerald A. Higgins of the National Institute on Aging also inserted the gene for beta-amyloid into mice. Linked to it, however, was another gene called a promoter, which caused beta-amyloid to be produced in unusually high quantities--about 80 times the amount that would normally be present in mouse brains.
By the age of 8 months, equivalent to middle age in humans, the animals had developed not only extensive plaques in their brains, but also extensive tangling of nerve cells, a secondary complication of Alzheimer's that is also common in humans.
By the time the animals were 1 1/2 years old, Higgins said, the concentration of plaques had become very dense, and as many as 40% of the cells in the cortex had died. As the animals aged, furthermore, they became hyperactive in their movements, they were irritable and developed abnormal gaits and posture.
"These aren't necessarily cardinal signs of Alzheimer's disease," Higgins said, "but they are certainly signs of severe neurological problems." The group is now testing the animals to see how their memory is affected, he added.
In addition to providing a new tool for scientists, the research would seem to provide a definitive answer to the persistent question of whether the plaques are the cause of Alzheimer's or simply a byproduct of some more fundamental disease process. The research suggests that the plaques are the cause.
In an editorial in Nature accompanying the paper, neuroscientist Dennis J. Selkoe of Harvard Medical School concluded that "the longstanding argument . . . has been settled."