Mechanistic Link Discovered between Calcium Signaling and Alzheimer Gene

Newswise — Scientists from the Institute for Aging and Alzheimer's Disease Research (IAADR) based in Fort Worth, Texas, have discovered a molecular mechanism that links the activity of a crucial protein involved in Alzheimer's disease with a fundamental signaling process in nerve cells.

Published online in The International Journal of Biochemistry & Cell Biology, the research was funded by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH) and the Alzheimer's Association.

The discovery builds on previous research from several NIA-funded laboratories that identified mutations in the Alzheimer's disease related gene presenilin-1 as the cause of impaired activity and reduced health of nerve cell in the brain. The study's lead investigator, Peter Koulen, Ph.D., of the IAADR at the University of North Texas Health Science Center had two major goals when he initiated the study in 2003: to identify the role of normal, so-called wild-type presenilin-1 in regulating neuronal function, and to reach the mechanism that drives this function. This appeared to be of particular relevance because only a small portion of Alzheimer's disease sufferers carries such mutations (often called familial Alzheimer's disease), while the majority of patients have sporadic Alzheimer's disease, in which no apparent direct genetic changes have been identified.

Alzheimer's disease is the most common form of dementia and currently affects more than 5 million Americans. While the severity of the disease increases with time leading to deficiencies in cognition and memory, there is no known cure.

While other research had clearly identified the role of presenilin-1 in the processing of the beta-amyloid precursor protein (APP) --- a protein critically implicated in the development of Alzheimer's disease --- Dr. Koulen's research team focused on presenilin-1 as a controlling factor for a different critical function of nerve cells. Nerve cells in the brain tightly control the concentration of calcium inside the cell. Changes in the amount of calcium are used by nerve cells to control critical activities including gene expression, learning and memory. Amazingly, early NIA-funded research had identified that this critical process called calcium signaling could also, under conditions of abnormal regulation, turn into an early trigger of brain aging and age-related cognitive decline. The formulation of this calcium hypothesis of brain aging and Alzheimer's disease has contributed significantly to our current understanding of several degenerative diseases affecting the nervous system.

Today's discovery explains not only how presenilin-1 controls one major component of calcium signaling in normal, functionally intact brain nerve cells, but also provides initial clues towards which specific parts of the presenilin-1 protein are needed to achieve this activity. Dr. Koulen and his team were able to measure the effects of the portion of presenilin-1 that protrudes into the inside of nerve cells on one critical protein that controls the concentration of calcium in nerve cells. Measuring the activity of individual molecules of this protein (the ryanodine receptor), the scientists were able to conclude that presenilin-1 is essential for the proper function of nerve cells through calcium signaling. The finding provides basic insights into the way nerve cells operate and clues to causes of this devastating disease. It also may provide a lead for future approaches to developing therapies.

In addition to NIA funding, the researchers were supported by several other entities in the U.S., including the national Alzheimer's Association and its North Central Texas chapter.

University of North Texas Health Science CenterThe University of North Texas Health Science Center is composed of the Texas College of Osteopathic Medicine, the Graduate School of Biomedical Sciences, the School of Public Health, and the School of Health Professions. Key research areas include Alzheimer's and aging, health disparities, osteopathic manipulative medicine and women's health. This year, the Texas College of Osteopathic Medicine was named a top 50 medical school in primary care by U.S. News and World Report for the sixth consecutive year. The institution contributes almost $500 million to Tarrant County and Texas economies annually. For more information, go to http://www.hsc.unt.edu/

Reference: V. Rybalchenko et al., The cytosolic N-terminus of Presenilin-1 potentiates mouse ryanodine receptor single channel activity. The International Journal of Biochemistry & Cell Biology, 2007. DOI: 10.1016/j.biocel.2007.06.023

PHOTOS: Photos of Koulen available upon request from UNTHSC.