Researchers Pinpoint How Estrogen Prevents Alzheimer's "Senile Plaques"

Evidence that the speed of a pathway changes the metabolic fate of a protein

Researchers in Paul Greengard's laboratory have shown that the hormone estrogen stimulates the passage of amyloid precursor proteins (APP)—which contribute to the formation of senile plaques found in Alzheimer's disease—through a part of the cell known as the trans-Golgi network, thus reducing beta-amyloid formation in that compartment. Above, a neuron from the cortical region of a rat brain shows APP predominantly localized in the Golgi compartment (bright area).

Estrogen prevents the build-up of Alzheimer’s disease’s “senile plaques” in the brain by scooting key proteins through their normal pathways before they can form the debilitating plaques.

This finding, by scientists in the laboratory of Rockefeller University Nobel laureate Paul Greengard, Ph.D., along with colleagues at Weill Medical College of Cornell University, provides evidence that the speed of a pathway can change the metabolic fate of a protein.

The results, derived from mouse cell lines and primary cultures from rat and human neurons, may have clinical applications for Alzheimer’s prevention in women.

“These results suggest a new approach in the development of therapeutic agents for the treatment of Alzheimer’s disease,” says Greengard, Vincent Astor Professor and director of Rockefeller University’s Fisher Center for Alzheimer Research.

Alzheimer’s – whose devastating effects include memory loss, dementia and ultimately death – is characterized by these so-called senile plaques that build up in the brain. Most researchers believe these plaques are the cause of the disease. In the late 1990s, Greengard’s laboratory was the first to demonstrate that estrogen reduces the production of the protein which accumulates to form these plaques using mouse, rat and human neurons. Several groups, including Greengard’s, then showed that estrogen administration resulted in similar reductions in this protein in animal models of Alzheimer’s disease.

The new findings, reported in the April 5 issue of The Journal of Biological Chemistry, provide the first step-by-step explanation of how estrogen prevents senile plaque build-up.

Senile plaques in the brain consist of clumps of protein fragments known as beta-amyloid peptides. These are formed when certain proteins (called amyloid precursor proteins, or APP) travel through a part of the cell known as the trans-Golgi network (TGN) on their way to the cell surface. Most scientists believe that the longer the proteins stay in the TGN, the more likely they are to develop into beta amyloid.

The Rockefeller team used an advanced “cell-free” laboratory technique that allowed them to look at individual components of cells (rather than whole cells) to analyze discrete steps in the APP pathway. They found that estrogen ushers the precursor proteins through the TGN before they can form beta amyloid. Once the proteins reach the cell surface, they are cut in half by enzymes and can no longer form senile plaques.

“Merely by speeding up APP’s pathway, estrogen can reduce the amount of protein secreted as beta amyloid,” says author Huaxi Xu, Ph.D., an assistant professor in Greengard’s laboratory and the Fisher Center for Alzheimer Research. “Over a lifetime, even a small percentage decrease could have significant health consequences.”

“Alzheimer’s is a disease of old age because it usually takes decades for these beta-amyloid plaques to build up,” adds first author Jeffrey P. Greenfield, Ph.D., a former graduate student of Greengard’s who is now an M.D. candidate at Weill Medical College of Cornell University. “That’s also why it’s a disease of the 20th century – in the past few people lived long enough to get Alzheimer’s.”

The new findings may explain the lack of clinical effectiveness of estrogen on women who already have Alzheimer’s. Explains Greenfield: “Estrogen can help keep the senile plaques from forming, but does not, so far as anyone knows, act to reverse the build-up. Like heart disease or osteoporosis, Alzheimer’s may be easier to prevent than to treat.”

The researchers caution, however, that estrogen supplementation in women has potential health complications. “Most currently prescribed hormonal supplements are a combination of estrogen and progesterone, which is considered safer than estrogen alone,” says Greenfield. “We don’t yet know how the combination of these two hormones might affect the development of the Alzheimer’s plaques,” and we don’t know how doses of pure estrogen might affect human patients.”

Greengard’s, Xu’s and Greenfield’s co-authors are Dongming Cai, Ph.D., Krista Kaasik, M.Sc., and Rachel S. Gross from Rockefeller, and Lawrence W. Leung, Ph.D., and Enrique Rodriguez-Boulan, M.D., from Weill Cornell Medical College.

Funding for this research was provided by the National Institutes of Health, the Alzheimer’s Association, the Ellison Medical Foundation and the American Health Assistance Foundation.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of whom are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences.