Study Suggests That Potential Alzheimer Drugs Might Be Dangerous

"Our paper suggests that these drugs could have significant side effects," says Raphael Kopan, Ph.D. "By using basic scientific methods such as the one we have developed, we hope to improve the ability of the scientific community to evaluate any Alzheimer drugs for their potential to cause life-threatening complications. Our system would also help identify drug dosages that might be safe in clinical trials." Kopan is associate professor of medicine and of molecular biology and pharmacology at Washington University School of Medicine in St. Louis.

Kopan led the study, which is described in the June 19 issue of Proceedings of the National Academy of Sciences. The first author was Brandon K. Hadland, an M.D./Ph.D. student at the School of Medicine. The St. Louis researchers collaborated with scientists at the Medical College of Georgia, the University of Tennessee and Harvard Medical School and Brigham and Women’s Hospital.

Alzheimer’s disease affects an estimated 4 million people in the United States. Researchers recently identified three genes that, when faulty, predispose individuals to this devastating neurological disorder. Two of them, presenilin-1 and presenilin-2, code for parts of a protein complex called gamma-secretase. In Alzheimer’s disease, this complex generates a protein fragment that accumulates as plaque in the brain. Using drugs, scientists hope to interfere with gamma-secretase production, thereby preventing plaque buildup.

Other parts of the body need gamma-secretase, however. Kopan and colleagues previously found that the complex is required for Notch, a receptor protein, to signal. Notch is needed for production of many cell types in our body, including blood cells such as T-cells–immune cells made and housed in blood.

The researchers feared that administering a drug that interferes with gamma-secretase production also would alter Notch function, hampering cell production in various tissues. As a model, the researchers focused on the immune system. They therefore determined the effects of a gamma-secretase inhibitor called compound #11 on cells from fetal mouse thymus, the organ where T cells develop. To simulate the continual drug therapy that would be required in humans, they treated cultured thymus lobes with a small dose of inhibitor every 12 hours.

After three days, the treated lobes had produced significantly fewer T cells than untreated ones. These results mimic previous observations of thymus cells lacking the appropriate Notch protein. The researchers therefore concluded that inhibiting gamma-secretase prevents T cells from maturing properly.

To see whether compound #11 affects later stages of T cell development, the researchers exposed thymus cells to the inhibitor on days three through six of culture. They found significantly low levels of one type of T cell, CD8, and normal quantities of a second type, CD4. They concluded that gamma-secretase also influences development at the stage when T cells differentiate into subtypes.

"We don’t want to scare the public about these exciting therapeutic advances," says Kopan. "Quite the contrary–we’re offering a way to evaluate potential Alzheimer drugs for toxicity before human testing. Doses that reduce gamma-secretase activity without eliminating it might be the safest."

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Reference: Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, Schroeter EH, Kopan R. g -Secretase inhibitors repress thymocyte development. Proceedings of the National Academy of Sciences, 13, June 19, 2001.

Funding from the National Institutes of Health, the Medical Scientist Training Program and the Alzheimer’s Association supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.