Apo E in Alzheimer's stunts nerve growth.

Many researchers agree that a molecule called apolipoprotein E (apo E) is somehow linked to the development of Alzheimer's disease (SN: 1/1/94, p.8). But they have yet to figure out why inheriting one form of this molecule increases an individual's risk of developing the debilitating dementia. Many people with apo E-IV are more likely to show symptoms of Alzheimer's at younger ages than people who inherit other forms.

Now, experiments involving peripheral nerve cells of rabbits have revealed a key difference between apo E-IV and the more common isoform known as apo E-III in regulating the growth of young nerve cell appendages, or axons. Apo E-III stimulates this growth; apo E-IV does not, says Robert W. Mahley, a cellular and molecular biologist at the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco.

Mahley and his colleagues had begun studying apo E molecules long before genetic studies linked different forms of apo E to Alzheimer's disease. His group had learned that cholesterol-rich lipoprotein particles stimulate the growth of branches from developing axons. These researchers then observed that adding apo E-III to laboratory dishes of nerve cells causes axons to grow longer rather than to branch.

Substituting apo E-IV for apo E-III, however, stunts both types of axon growth, report Mahley, Gladstone's Britto P. Nathan, and their colleagues in the May 6 SCIENCE. "We find quite a striking difference [between the two]," says Mahley. In addition, unpublished work by this team suggests that apo E-IV leads to denser deposits of the beta-amyloid peptide implicated in Alzheimer's disease.

"To us, the [Gladstone] work is important because it demonstrates that there are isoform-specific effects on the development and growth of neurites [young axons]," comments Warren J. Strittmatter, a neuroscientist at Duke University Medical Center in Durham, N.C.

A Duke group has suggested that apo E-IV somehow fails to protect nerve cells in the same way that apo E-III can and therefore does not slow the progressive loss of brain function that eventually leads to Alzheimer's.

"This [report] could give insight into the neuronal mechanism," says Zaven S. Khachaturian of the National Institute on Aging in Bethesda, Md. The brains of people with apo E-IV may be less able to maintain or repair vital links between nerve cells.

When peripheral nerves are injured, white blood cells nearby make lots of apo E so they can take up lipids released by the deteriorating nerve cells, Mahley explains. Those lipids help rebuild nerve tissue. In addition, apo E-III may help cells construct and maintain microtubules, which make up an intracellular freight system for shuttling molecules to the far reaches of axons. By not playing that role, apo E-IV may impair nerve cells, Mahley and Strittmatter suggest.

In these experiments, apo E's effects depend on the presence of lipid particles. When the researchers added one type of apo E and no cholesterol-carrying particles to the nerve cells, the axons grew as if nothing had been added. Thus apo E must need to link with lipid particles in order to attach to docking sites on the cell's surface and get inside.

"We're beginning to unravel how apo E-III versus apo E-IV may impact the biology of the nervous system," Mahley concludes.