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
Contact: Corinna Kaarlela
University of California - San Francisco