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A team led by Dr. Karen Ashe, shown here with one of her research subjects, has identified a substance that may cause memory problems years before the onset of Alzheimer's disease.
Nabbing the thief of memory
By Deane Morrison
March 16, 2006
Somewhere, a middle-aged woman is trying to tell her 10-year-old daughter why grandma doesn't recognize her anymore, leaving out how she struggles with her own fears of getting Alzheimer's disease like her mother. Probably no one saw it coming, because Alzheimer's disease, or AD, takes hold in an insidious fashion, cloaking the clues to its presence in the garb of normal age-related memory impairment. But in a laboratory at the University of Minnesota, Karen Ashe and her research team have just picked up one of those clues. Their work identifies a possible future target for therapies to defeat the disease before it causes irreversible damage. Currently, about 4.5 million Americans live with Alzheimer's disease, a number that could rise to 14 million in the next 20 years. "No one knows for sure when Alzheimer's disease begins," says Ashe, a professor of neurology and neuroscience and director of the University's Center for Memory Research and Care. "One study showed you could predict it 15 years before the earliest symptoms. Those were normal individuals who had very subtle abnormalities on cognitive tests." Some people who are known to be genetically at risk for AD show abnormalities in brain function on a brain scan, all of which suggest changes in the way the brain operates long before nerve cells begin to die. One thing that consistently turns up in the brains of deceased AD patients is numerous insoluble clumps, or plaques, composed of a specific protein called amyloid-beta (A beta). At first it was thought that the plaques caused AD. But that turned out not to be the case. "About four years ago, we realized there was no correlation between the amount of plaque and the amount of memory dysfunction," says Ashe. That doesn't mean, however, that the A beta molecules play no role in the disease. Amyloid-beta thus became a focus of Ashe's efforts.
"I could only have done this [research] at the University of Minnesota, primarily because the work depended on the backbone and foundation of my lab, which is several lab technicians, some of whom have been with me for many years," says Ashe. "I don't know of another institution on the coasts or with any prestige where I could have such a fine group of technicians."About 12 or so mutations in the human gene for A beta are linked to early-onset Alzheimer's disease. Ashe chose one such mutant gene, which causes the brain to produce A beta in large quantities-a close approximation to the increased outputs of A beta that occur in normal aging. Using mice that were genetically engineered with the mutant gene, Ashe and her team set out to find just how A beta does its mischief. In mice with the mutant gene, memory loss begins at six months of age. But nerve cells don't begin dying until the ripe old age of 14 months. Several lines of evidence led Ashe to suspect that A beta was responsible for the early memory deficits in the engineered mice. But if not plaques, what other manifestations of A beta could be causing the impairment? The researchers reasoned that it had to be a form of the protein that appeared at the same time of the memory loss (six months of age) and that persisted in the brain at a steady level until the mice reached 14 months of age. Ashe dubbed the mystery form "A-beta-star" and the search was on. To find A-beta-star, Ashe drew on the expertise of Sylvain Lesn?, a postdoctoral fellow in her laboratory. Working with the brains of engineered mice, he isolated pools of A beta from inside cells, outside cells, in the cell membrane, and in deposits rich in the A beta protein. Most intriguing, Lesn? found that A beta in the spaces between nerve cells can be quite sociable with each other. That is, molecules of A beta clump together in aggregates of three, six, nine or 12. The next step was to test all these bundles of A beta, as well as the individual molecules, to see which were most capable of causing memory problems. Of course, one cannot do such a test in human beings. To test for memory impairment, Ashe uses mice who have learned the locations of objects and then demonstrate their degree of memory by searching in the right (or wrong) places for the objects after they have been removed. To see how A beta affected their memory, the procedure was to place a tube in the animals' brains, deliver each form of A beta-one per animal-- into the fluid bathing the brain, and note its effects on memory. But mice don't tolerate such tubes very well, so Lesn? sent the samples to Michela Gallagher at Johns Hopkins University, who did the experiments with rats. The tests showed that aggregates of 12 A beta molecules not only appeared in the mice's brains at about six months of age, but they were by far the most potent in causing memory loss in rats. Ashe and her colleagues hypothesize that these aggregates of 12 A beta molecules are the elusive A-beta-star. But the team also found that the damage was not permanent; 10 days after being treated with the aggregates, the rats regained their memory ability. As Ashe puts it, the A beta protein, even A-beta-star, didn't kill neurons-it just put them to sleep. At this point there is no way to detect A beta aggregates in living humans, so Ashe and her team have turned their attention to developing a blood test for it. Besides her work with amyloid-beta protein, Ashe and another postdoc, Martin Ramsden, are working with a second protein, called tau, that forms tangles of fibers in the brains of AD patients. Some form of the tau protein kills nerve cells in mice, but Ashe's team has found that the "neurofibrillary tangles" are not the culprit. Ramsden is looking for a form of tau, called tau-star, that does impair memory. The researchers also plan to search for one or more drugs to help AD patients. A future drug may help ward off the disease by preventing molecules of A beta from aggregating into A-beta-star or by keeping A-beta-star from interfering with neuron functioning. For this phase, Ashe is working with College of Pharmacy faculty, especially from the department of medicinal chemistry. "We hope to work with Gunda Georg, who will become head of the medicinal chemistry department this fall," says Ashe. "She's a star. "We're also on the verge of opening a Memory Clinic under the umbrella of the Center for Memory Research and Care. J. Riley McCarten, who has a joint appointment at the VA Medical Center, has a team to take care of families and patients." As envisioned, the Memory Center will screen for AD and other memory disorders and sponsor clinical trials of drugs found effective against memory loss in mice. Although laurels for Ashe's work pour in, she remains solidly grounded. She credits her success to the people in her lab, who perform the herculean labor of maintaining colonies of mice and carrying out numerous exacting experiments with precision. "I could only have done this at the University of Minnesota, primarily because the work depended on the backbone and foundation of my lab, which is several lab technicians, some of whom have been with me for many years," says Ashe. "I don't know of another institution on the coasts or with any prestige where I could have such a fine group of technicians." So take a bow here, Colleen Forst, Jen Paulson, Nardina Nash, Mathew Sherman, Lisa Kemper, and Linda Kotilinek. "What's unique from my experience is the team approach," says Kotilinek of working in Ashe's lab. Kotilinek, whose work focuses on behavioral testing of mice, says that with the enormity of work in Ashe's lab, everybody has to know something about everybody else's experiments. It's this kind of overlapping that allows the team to do experiments seven days a week. "I feel that what we're doing is extremely important, and that makes the difference," Kotilinek adds. "I think the University is very supportive of technicians," Ashe says. "All but one own their own homes, and three are women my age. I hope we'll grow old together." The team's latest work is published in this week's issue of the journal Nature.