Gene Associated with Alzheimer's Disease Can Protect Brain Cells

A protein made by a gene called apolipoprotein E (apoE) protects cultured nerve cells from the damaging effects of a form of oxygen molecules known to contribute to Alzheimer’s disease, report scientists from The Rockefeller University. The findings, published in the September Nature Genetics, reveal a previously unknown function of apoE and may lead researchers to new therapies to treat Alzheimer’s disease.

“The apoE protein, which transports cholesterol and other fatty substances through the blood stream, appears to protect neurons by acting as an antioxidant,” says senior author Jonathan D. Smith, Ph.D., assistant professor in the Laboratory of Biochemical Genetics and Metabolism. Antioxidants are substances thought to slow, block or reverse damage to cells caused by reactive oxygen molecules and free radicals, waste products generated by cells during metabolism.

“Three common forms of the apoE protein, called E2, E3 and E4, are produced by three different versions, or alleles, of the apoE gene,” says Smith. “We’ve shown for the first time that each form of the apoE protein has a different level of antioxidant activity, offering a range of protection to cultured neurons from oxidative cell death. We now want to see if the proteins offer the same amount of protection to neurons in laboratory animals.”

In the study, Smith and his co-author, Masaaki Miyata, M.D., Ph.D., found that the E2 protein is the most effective, E3 is somewhat effective and E4 is the least effective in protecting cultured neurons–nerve cells originally derived from the brains of rats–from the oxidative damage caused by reactive oxygen molecules, free radicals or [[beta]]-amyloid peptide. Other researchers reported that [[beta]]-amyloid peptide, a small protein that is a major component of the brain plaques that characterize Alzheimer’s disease, spontaneously produces free radicals.

Previous studies linked the E4 allele to early onset of Alzheimer’s disease and decreased longevity. The E4 allele, carried by nearly 30 percent of the population, also is associated with slightly higher levels of low density lipoprotein (LDL), the “bad” cholesterol, and an increased risk of death from cardiovascular disease. Researchers have found that 50 to 64 percent of Alzheimer’s patients carried at least one copy of the E4 gene, suggesting a connection between the gene and the risk of developing the disorder. In studies of aging populations, people who live to be 100 or older are more likely to possess a copy of the E2 allele and less likely to possess the E4 allele, suggesting that a person’s apoE genetic profile may influence his or her life span.

In the experiments, Miyata and Smith treated neurons with the apoE forms at physiological levels, the same amount occurring in the brain. They found all three forms protected the cells from hydrogen peroxide, a reactive oxygen molecule that can be lethal to brain cells, with E2 the most effective and E4 the least effective. The researchers obtained similar results when they mixed physiological amounts of each apoE form with [[beta]]-amyloid peptides.

However, when they combined [[beta]]-amyloid peptide with larger amounts of each apoE form–at levels more than three times that found in the brain–more cells died, particularly with the E4 form.

“Other researchers have shown that the toxicity of [[beta]]-amyloid peptides to neurons is directly related to clustering or aggregation of the peptide around the cells,” says Smith. “We think that, at high levels, apoE interacts with [[beta]]-amyloid peptide and enhances its aggregation.”

Although the results show apoE can act as an antioxidant, how it does this is still unknown. In their current work, Miyata and Smith demonstrated for the first time that apoE can interact with specific metal ions. “Hydrogen peroxide reacts with metals in the body, producing even more toxic molecules that cause cell death,” says Smith. “ApoE may reduce the amount of free metals available for this reaction.”

ApoE’s metal-binding ability may also play a role in the development of Alzheimer’s disease. “Metals are known to promote the formation of new [[beta]]-amyloid fibers,” says Smith. “It’s possible that, at high levels, apoE might bring metals in contact with [[beta]]-amyloid peptide, creating new fibers.”

In addition, Miyata and Smith found that E2 had the highest antioxidant activity of the three apoE proteins in test tube systems without neurons, supporting their findings in the cell protection experiments.

The apoE gene was discovered at Harvard University in 1983 by Jan L. Breslow, M.D., now Frederick Henry Leonhardt Professor and head of the Laboratory of Biochemical Genetics and Metabolism at Rockefeller.

Smith is an Established Investigator of the American Heart Association and Miyata is supported by The Japan Heart Foundation.