PITTSBURGH, February 20, 1998 — A naturally produced enzyme, bleomycin hydrolase, whose only known function is to detoxify a widely used cancer agent, has now been linked to a four-fold increased risk of developing Alzheimer’s disease (AD), according to an article by University of Pittsburgh researchers in the March issue of Nature Genetics.
Bleomycin hydrolase breaks down bleomycin, a potent cancer drug used to treat testicular and other cancers. Investigators at the University of Pittsburgh and elsewhere have long researched ways to selectively activate bleomycin hydrolase in healthy tissues that are damaged by bleomycin. This agent can cause life-threatening lung fibrosis in patients treated with the drug.
"Our research discovery is significant because it provides the first susceptibility gene for sporadic, or non-familial, cases of Alzheimer’s disease in people who lack the only other known inherited risk factor, APOE*4, for sporadic disease," noted Susana Montoya, co-author of the study and a graduate student at the University of Pittsburgh. "The bleomycin hydrolase risk factor also is greater than any known environmental risk factor for Alzheimer’s disease."
More than 90 percent of AD cases are sporadic and of late onset. Previous research has shown that individuals with the APOE*4 form of the apolipoprotein gene are at higher-than-expected risk of developing sporadic AD. Apoplipoprotein E is thought to facilitate the deposition of amyloid plaques within the brains of AD patients. Investigators have long sought risk factors for members of the population who do not carry APOE*4 (about 40 percent) yet still develop sporadic AD. Four million Americans are affected by AD, according to the National Alzheimer’s Association.
"This discovery gives us another significant opportunity to identify people at risk for Alzheimer’s disease. With this information, we can explore potential mechanisms to intervene early to prevent disease development or significantly delay its course," noted Steven DeKosky, M.D., co-author, professor of psychiatry, neurology and human genetics, and director of the Alzheimer’s Disease Research Center (ADRC) at the University of Pittsburgh. Dr. DeKosky also is chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Committee.
"It’s obvious that the bleomycin hydrolase protein did not evolve to counter the effects of a single cancer agent," said Robert Ferrell, Ph.D., professor of human genetics and senior author on the paper. "Our research finding suggests a plausible role for this enzyme in processing the amyloid precursor proteins that give rise to the plaques characteristic of Alzheimer’s disease."
"This research could be the first step toward designing a therapy in which we would selectively alter bleomycin hydrolase activity in brain cells to prevent the generation of disease plaques," added John S. Lazo, Ph.D., co-author, professor and chairman of the department of pharmacology at the University of Pittsburgh, and co-director of Molecular Therapeutics/Drug Discovery at the University of Pittsburgh Cancer Institute. "Our group and others have already explored this approach in treating cancer patients," added Dr. Lazo, who first sequenced the bleomycin hydrolase protein and who has worked for 10 years on novel ways to selectively block the activity of this enzyme to make bleomycin effective against tumors.
In their research, the Pitt investigators studied the bleomycin gene in 357 Alzheimer’s disease patients and 320 controls obtained through the ADRC and the Indiana Alzheimer’s Disease Center Cell Repository. The bleomycin gene has two forms, or alleles, called A and G. The investigators found that individuals with two copies of the G bleomycin hydrolase allele (G/G) and without APOE*4 are four times more likely to have AD. About six percent of the population would be expected to fit this genetic profile (G/G, -APOE*4).
The Pitt scientists originally became interested in the possible connection between bleomycin hydrolase and AD for several reasons. To start, they were looking at the possible association between the bleomycin hydrolase gene and several diseases, including lung fibrosis. They knew that bleomycin hydrolase comes from a class of enzymes called cysteine proteases, which have been thought to play a role in neurodegenerative disorders. Then, while working on cloning the bleomycin hydrolase gene, the Pitt team learned from a group of Boston University-based investigators that they had purified bleomycin hydrolase from the brains of AD patients and had evidence indicating that this enzyme was involved in processing an amyloid precursor protein. Abnormal breakdown of the amyloid precursor protein leads to production of a small fragment of amyloid which piles up in the brains of AD patients.
The genetic sequence for bleomycin hydrolase is strikingly similar among organisms. The gene occurs in yeast, bacteria and humans, and the enzyme is found in cells throughout the body.
"These features strongly suggest that bleomycin hydrolase naturally has one or more critical functions in the body," added M. Ilyas Kamboh, Ph.D., study co-author and professor of human genetics at Pitt. "The G/G bleomycin hydrolase profile could be involved in AD in a number of ways. For instance, the G/G combination might reduce the life expectancy of bleomycin hydrolase or somehow otherwise compromise its ability to break down the amyloid precursor protein. Alternatively, this genetic change may be associated with another undetected change in the bleomycin hydrolase gene or with a mutation in a neighboring gene, either of which instead could be responsible for problems resulting in Alzheimer’s disease."
However, Dr. Kamboh cautioned that this positive association with AD needs to be confirmed by other independent research groups.
For additional information about the University of Pittsburgh’s Graduate School of Public Health, please access http://www.publichealth.pitt.edu. The website for the department of pharmacology at the University of Pittsburgh School of Medicine is http://pharmacology.medicine.pitt.edu.
This research was funded by grants from the National Cancer Institute, the National Institute on Aging and the Fiske Drug Discovery Fund.