New hope for Alzheimer's Disease- UTM researcher extends the calcium hypothesis
27 Jul 2004
A University of Toronto at Mississauga (UTM) biologist reports an interesting link between calcium and the treatment - and possibly prevention - of Alzheimer's disease.
The study will appear in the August 6, 2004 issue of the journal Biochemical and Biophysical Research Communications. The findings of the study, co-authored by UTM biology professor Danton O'Day and University of Toronto doctoral candidate Michael A. Myre, will provide new targets for future research and may assist in the development of pharmaceuticals to control, if not stop, the onset of Alzheimer's disease.
When the level of calcium in the brain is not properly controlled, it leads to nerve cell dysfunction and death. With Alzheimer's disease, calcium levels are unregulated. Calcium flows into brain cells in an unregulated way affecting cell function and survival. This is known as the calcium hypothesis of Alzheimer's disease.
Existing literature supports this model, but does not extend it or take it beyond calcium. This study does.
Stopping calcium's negative effects should stop Alzheimer's disease. So in their research, O'Day and Myre looked at what calcium does, and in doing so, determined calmodulin as the key.
"In cells, calmodulin is a primary calcium sensor that works by binding to other target proteins. It detects how much calcium is present and works according to what it finds," says O'Day. "Calmodulin works like a switch. It turns other proteins on or off. So when it detects too much calcium, it activates and deactivates things it shouldn't."
He explains that when two proteins bind together it usually occurs via a specific and easily identifiable region or "domain." Not so with calmodulin. With calmodulin there is no specific sequence. Instead there are arrangements of certain kinds of amino acids that can only be revealed by a trained eye or, more efficiently, a computer program.
"Altering calcium levels impacts calmodulin and its binding proteins. If altered calcium levels are the underlying cause of Alzheimer's disease, we would expect calmodulin to be involved," says O'Day.
They examined the primary proteins in two major models of Alzheimer's disease (see attached figure) to see if they could answer the question, "Can we find within these proteins a region that allows them to bind to calmodulin?"
Both visually and using a program at the Calmodulin Target Database (Ontario Cancer Institute, Toronto) they examined the amino acid sequences of all of the primary proteins in the major Alzheimer's disease models. Unexpectedly all of them had at least one region or "domain" that should allow them to bind to calmodulin. Statistically, this means that six to eight out of ten of these key proteins will be calmodulin-binding proteins.
"Calcium isn't the key. Calmodulin is," says O'Day. "Calcium will activate calmodulin and, in turn, calmodulin should regulate 60 to 80 per cent of these key proteins that are involved in Alzheimer's disease."
These findings open new avenues for research on this progressive, degenerative brain disease. According to the Alzheimer Society of Canada, approximately 238,000 Canadians over age 65 have Alzheimer's disease and it is estimated that over 509,000 Canadians will be diagnosed with the disease by the year 2031 if a cure is not found.
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