St. Louis, April 28, 1998 -- Since 1992, scientists have known that people with a particular form of the protein apoE are at increased risk for developing Alzheimer's disease. They have been frustrated, however, because there has been no way to find out how the biological effects of this variant, called apoE4, differ from those of apoE3, the most common apoE in humans. Researchers at Washington University School of Medicine in St. Louis now have offered a solution by generating mice that make only human apoE3 or human apoE4. Their experiments with these mice show that apoE3 promotes nerve cell outgrowth, whereas apoE4 does not.
Most people have either two apoE3 genes, two apoE4s or one of each. The apoE2 gene is much rarer. Inheriting two apoE4s seems to be the worst luck of the draw. As well as lowering the age at which Alzheimer's disease develops, this permutation appears to speed the onset of Parkinson's disease and bodes a poor neurological outcome after cardiac bypass or cerebral hemorrhage.
"Our thinking is that apoE3 is much more effective at promoting regrowth of nerve cell extensions after injury," says David M. Holtzman, M.D., assistant professor of neurology and molecular biology & pharmacology. "Or it might be protective in the setting of brain diseases by preventing loss of connections between neurons."
Holtzman is chief author of a paper in the May 1 issue of Journal of Neuroscience. Research associate Yuling Sun, is first author.
To generate the experimental animals, Sun inserted human apoE3 or apoE4
genes into mice. Through other genetic manipulations, she made the mice express
the human gene only in astrocytes, the housekeeping cells that normally make
apoE in the brain. The transgenic animals then were crossed with mice that
lacked the genes for mouse apoE. Eventually, the researchers obtained litters of
two types. One contained pups that made no apoE plus pups that made only human
Contact: Linda Sage
Washington University School of Medicine