Scientists have found that one form of a gene linked to Alzheimer's disease fails to get mouse nerve cells to grow, although a more common form does stimulate growth. The research, reported in the current Journal of Neuroscience, could help explain why some people recover better than others from brain injuries and might also shed light on how Alzheimer's develops.
The gene in question, apolipoprotein E (apoE), codes for a protein in the brain's astrocyte cells that seems to help spur nerve cell growth and clear up debris from neuronal injuries brought by head trauma, stroke, or cerebral hemorrhage. But no one has been able to pin down how various versions, or alleles, of the apoE gene--E2, E3, and E4--differ in function. The problem is particularly challenging because mice make only one form of apoE, which only partly resembles human apoE.
One way to bypass that hurdle is to make mice more like humans. To do so, a team led by neuroscientist David Holtzman of Washington University in St. Louis injected genes for human apoE3 or apoE4, which is about a third as common, into fertilized mouse eggs. Next they bred these transgenic animals with mice lacking their own apoE gene, creating animals whose astrocytes made only human apoE. The team removed these astrocytes and mixed them with neurons to try to mimic how the cells interact in the brain.
Holtzman's group found that neurons exposed to apoE3 grew dendrites and axons about twice as long as neurons exposed to apoE4 or no apoE. "It could be that the ability of neurons to be repaired after injury might be related to your apoE genotype," says Holtzman. And that could influence the progression of Alzheimer's, he adds, by influencing how brain cells react to the loss of connections between neurons that accompanies the disease.
"This is an excellent paper that presents new data about the potential differences in function of apoE3 and apoE4 in the brain," says Allen Roses, vice president at Glaxo Wellcome Research and Development in Research Triangle Park, North Carolina. The model may help reveal the role of apoE in response to brain injury and stress, he says.