Protein Regulates How Neurons Relay Signals Through Brain Cells, UCI Team Finds

Irvine, Calif., April 4, 2002 -- UC Irvine researchers have found a novel role for a protein linked to another known protein that causes the brain plaques in Alzheimer's disease.

The findings provide a greater understanding of the molecular events that underlie this degenerative brain disease, and could affect the way researchers are currently looking for treatments for Alzheimer's. The study appears in the April 2 issue of the Proceedings of the National Academy of Sciences.

UCI neurobiologists Frank LaFerla and Malcolm Leissring identified an important function for this protein, called AICD, whose normal activity was previously unknown. The researchers found that AICD is involved in regulating calcium signaling, which nerve cells in the brain use to communicate and relay chemical "messages" through a cell and is vital in maintaining cell health.

"We have been able to describe an important physiologic function for this AICD fragment, which was previously unknown," said LaFerla, associate professor of neurobiology and behavior. "Identifying a novel role for any Alzheimer's related protein is important because it provides a new avenue for therapies."

Alzheimer's disease is the most common cause of dementia, afflicting more than four million Americans. The majority of Alzheimer's cases are sporadic, striking individuals with no hereditary connection. Generally, this form afflicts individuals over 65 years of age. A small percentage of these cases are passed down from one generation to another.

Most cases of inherited Alzheimer's are due to inheriting a defective copy of a gene called presenilin-1, which leads to a very aggressive form of the disease. This form usually begins decades before the sporadic version. Most of these patients develop AD in their 30s and 40s, although sometimes the disease begins as young as 16. The inherited cases, although rare, provide researchers with a tool--a defective gene--to chart the initial steps by which the defective gene leads to Alzheimer's.

Both inherited and sporadic Alzheimer's are characterized by the occurrence of a small protein called beta-amyloid that gets deposited in selective brain regions, particularly those associated with memory. What triggers beta-amyloid's accumulation is unclear, although beta-amyloid is derived from the beta-amyloid precursor protein.

All humans have two distinct presenilin genes, called presenilin-1 and presenilin-2. Only the mutated forms of the presenilin genes lead to early-onset Alzheimer's. The proteins encoded by these genes, among other things, appear to regulate the cleavage of the beta-amyloid precursor protein. This cleavage, much like a scissor cutting a ribbon, creates both beta-amyloid and AICD. The newly liberated AICD protein then presumably regulates other genes, which may play roles in Alzheimer's disease.

In one set of experiments, LaFerla's team studied calcium signaling in cells in which presenilin function was inactivated either by the removal of the presenilin genes or by using inhibitor drugs that interfere with its ability to create beta-amyloid and AICD. In both cases, calcium signaling was significantly diminished. To determine if it was the presenilin protein that abolished the calcium signaling or a product generated by it (either beta-amyloid or AICD), LaFerla's team studied calcium signaling in cells lacking the beta-amyloid precursor protein and showed that calcium signaling was comparably altered, suggesting all or part of the beta-amyloid precursor was responsible for this effect.

To address this issue, they added back various fragments of the beta-amyloid precursor protein to the cells and showed that they could rescue the deficit, provided that the AICD portion of the precursor protein was intact. Based on these studies, the researchers concluded that AICD plays a critical role as a signaling molecule, traveling to the nucleus and presumably inducing the expression of other genes involved in calcium signaling. This is the first physiological role assigned to AICD.

Assisting LaFerla and Leissring were Michael C. Sugarman, Yama Akbari, Tonya R. Mead and Mehrdad Jannatipour of UCI; M. Paul Murphy and Todd E. Golde of the Mayo Clinic in Jacksonsville, Fla.; Brigitte Anliker and Ulrike Muller of the Max-Planck-Institute for Brain Research in Frankfurt, Germany; Paul Saftig of the University of Gottingen in Germany; Bart De Stooper of the Flanders Interuniveristy Institute for Biotechnology in Belgium; and Michael S. Wolfe of Harvard. The National Institutes of Health, the American Health Assistance Foundation, the American Federation for Aging and the Ellison Medical Foundation supported the research.


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