Laboratory mice genetically engineered to have human apolipoprotein E4 (apoE4) in the brain, a protein associated with increased risk of Alzheimer's disease, show learning and memory problems strikingly similar to those seen in human Alzheimer's patients, according to researchers at the J. David Gladstone Institutes and UC San Francisco.
People who inherit the gene for apoE4 are known to be at much greater risk of Alzheimer's than people who inherit the gene for the more common form of this protein, called apoE3. To characterize the effects of these proteins on cognitive functions, the Gladstone researchers developed entirely new strains of mice that express human apoE3 or apoE4 in the brain instead of mouse apoE. The researchers then observed the behavior of these mice in a variety of controlled laboratory situations that require specific cognitive skills.
The apoE4 mice performed poorly in tests requiring spatial learning and memory skills and were less likely to explore their environment than the apoE3 mice. The effects were most noticeable in mice that were older and female. "We are very excited about these results because they mimic in several respects what is seen in humans with Alzheimer's disease," said Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease, UCSF associate professor of neurology, and senior author of the study.
"Alzheimer's typically comes on with advancing age, and women who have apoE4 appear to be at particularly high risk for the disease," said Jacob Raber, PhD, a staff research scientist at the Gladstone and first author on the study. The newly engineered apoE4 mice could serve as a valuable tool for testing potential therapies for this devastating disease, which affects some four million Americans. "This is the first model in which we were able to simulate the detrimental effects of human apoE4 on brain function," Mucke said. "That should put us in a good position to test out treatments to combat these detrimental effects."
The work was conducted by investigators at the Gladstone Institute of Neurological Disease, a major new research enterprise based at the San Francisco General Hospital campus of UCSF. The results are published in the Sept. 1 issue of Proceedings of the National Academy of Sciences U.S.A.
In one experiment, mice had to learn the location of a hidden target in a maze that tests their ability to remember and process spatial information. Similar skills are strongly affected in Alzheimer's patients, who often get lost because they have trouble finding their way home.
ApoE3 mice learned how to find the hidden target with relative ease, whereas their apoE4 counterparts had difficulty with the exercise, and some never found the target at all even after repeated tries. Consistent with the age dependence of Alzheimer's disease, only older apoE4 mice showed deficits in learning and memory, whereas young apoE4 mice were not impaired.
In another experiment, mice were placed in an open field inside a cage, and their movements were monitored with motion sensors. Older apoE4 mice showed much less exploratory curiosity in this test than age-matched apoE3 mice. The investigators speculate that these findings might also relate to Alzheimer's patients, who often lose interest in their environment and abandon activities that once engaged them.
In both experiments, the researchers noticed a distinct difference in behavior between female and male mice, with the females experiencing a higher level of impairment. These results are consistent with clinical studies by other investigators which suggest that apoE4 increases Alzheimer's risk and decreases responsiveness to treatments more strongly in women than in men.
The researchers already have begun to manipulate the levels of apoE4 in the brains of these mice to see what impact these changes might have on their behavior. Mucke said it may be possible to design drugs that inhibit apoE4 or simulate apoE3 to counteract the neurological effects of Alzheimer's. "The real test of this model will come when we can test treatment strategies and see if they will work in humans," he said.
In addition to Mucke and Raber, the researchers on the study, all of the Gladstone Institutes, included Derek Wong, research associate; postdoctoral fellows Manuel Buttini, PhD, Matthias Orth, MD, PhD, and Stefano Bellosta, PhD; Robert E. Pitas, PhD, UCSF professor of pathology and Gladstone senior investigator; and Robert W. Mahley, MD, PhD, UCSF professor of pathology and medicine and president of the Gladstone Institutes. The research was supported by the Gladstone Institutes and Cambridge Neuroscience in Cambridge, Mass.
Journal
Proceedings of the National Academy of Sciences