Role of key protein that may stave off inherited form of Alzheimer's disease discovered by UC Irvine researchers

July 31, 2000

Research on early-onset form of neural disease may lead to prevention methods

A key protein involved in the regulation of calcium in brain cells may influence the development of therapies and preventive methods for early-onset familial Alzheimer's disease, an inherited form of this neurological disorder that affects adults in their 30s and early 40s, UC Irvine neuroscience researchers have found.

Malcolm A. Leissring and Frank M. LaFerla, in collaboration with Ian Parker, all of UCI's Department of Neurobiology and Behavior, have discovered that a protein named calsenilin can offset calcium imbalances in brain cells that can lead to the neural changes associated with Alzheimer's disease. Among its roles, calcium helps regulate numerous cellular activities, but these imbalances, however, are not related to dietary intake of calcium, the UCI researchers point out. Their findings appear in the July 18, 2000 issue of Proceedings of the National Academy of Sciences.

Most early-onset familial Alzheimer's disease cases are triggered by mutations in the genes that produce the protein presenilin. Mutations in these genes disrupt the proper handling of calcium inside brain cells, which can contribute to the identifying factors of Alzheimer's disease. These pathological features include the development of brain plaques caused by increased production of ß-amyloid proteins, neural fibril formation and cell death.

The UCI researchers have found in tests using frog eggs that the calsenilin protein, when bound to specific sites on the presenilin protein, can counteract the effects of mutant presenilin by stabilizing the activity of the mechanisms, which are called signaling pathways, that distribute calcium within cells. Calsenilin does this by reversing the increase of calcium signaling caused by presenilin mutations. Researchers from Harvard Medical School and Mount Sinai School of Medicine in New York, who worked with UCI researchers on this study, identified and named this multifunctional protein as one that binds with presenilin in a previous study; Calsenilin's ability to influence calcium signaling was not determined until the UCI study. Among its other roles, calsenilin also controls the activity of proteins that helps ions pass through the outside of cells.

"Our finding provides evidence that calsenilin could be an important mediator of mutant presenilin's effects on calcium signaling," Leissring said. "This could lead to pharmaceutical therapies and preventive measures to offset these mutations and stop the advancement of early-onset familial Alzheimer's disease. We hope that the information gained from this finding can eventually be applicable to understanding the causes of all forms of Alzheimer's disease."

Early-onset familial Alzheimer's disease is responsible for between 5 percent and 10 percent of all Alzheimer's cases; roughly 50 percent of those are due to presenilin mutations. In virtually all cases, according to the UCI researchers, people born with mutant presenilin genes will develop the early form of this neural disease.

According to the National Institute on Aging, an estimated 4 million people in the United States suffer from Alzheimer's disease, an incurable form of dementia that primarily strikes the elderly and causes severe memory loss. It is estimated that several hundred thousand of these Alzheimer's cases are due to mutations in the presenilin genes.

Researchers believe that the majority of the cases involve multiple factors. While genetic predisposition has been well established, other potential risk factors cited include stress, prior head injury and an abnormal concentration of metals in the brain, including zinc, copper and lead.

The UCI researchers hope that future research will establish exactly how calsenilin produces its effects. Based on their other research with presenilin, the researchers speculate that calsenilin might regulate the total amount of calcium that is stored inside cells.
-end-
Wilma Wasco of the Harvard Medical School, Joseph D. Buxbaum of the Mount Sinai School of Medicine and UCI research assistant Tritia R. Yamasaki assisted Leissring, LaFerla and Parker with this research.

The study was supported by the National Institutes of Health, a National Research Service Award and a Glenn Scholarship from the American Federation for Aging Research.

Tom Vasich
949-824-6455
tmvasich@uci.edu


A complete archive of press releases is available on the World Wide Web at www.communications.uci.edu

University of California - Irvine

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