An international team of researchers lead by the University of Toronto's Dr. Peter St. George-Hyslop have isolated a key protein involved in the degeneration of nerve cells in Alzheimer's disease, according to a study published in the Sept. 7 issue of Nature.
"We've found a completely unknown protein that's involved in the biochemical processing of the beta-amyloid precursor protein which causes Alzheimer's disease," said lead author Professor Peter St. George-Hyslop, director of the Centre for Research in Neurodegenerative Diseases (CRND) in the University of Toronto's Faculty of Medicine and a neurologist at the University Health Network. "This opens the way for the development of drugs that will target the new protein to manipulate the process that leads to the disease."
St. George-Hyslop and his team named the new protein nicastrin after a small southern Italian village called Nicastro which played an important early role in the discovery of the two genes that cause aggressive early onset forms of Alzheimer's. The researchers isolated nicastrin when they were searching for proteins that adhere to the two proteins, presenilin 1 and presenilin 2, already known to be involved in Alzheimer's. "We set out to find new proteins which bind to the presenilin proteins because mutations in the presenilins cause Alzheimer's disease by inducing abnormal processing of the beta-amyloid precursor protein and the accumulation of a toxic derivative, amyloid beta-peptide, in the brain of patients with Alzheimer's disease," St. George-Hyslop said.
Until now, the exact mechanism by which presenilin mutations altered beta-amyloid precursor protein processing and caused Alzheimer's was unclear. The researchers soon found that nicastrin binds to the beta-amyloid precursor protein and regulates the production of the potentially dangerous amyloid beta-peptide fragment. "More importantly," St. George-Hyslop said, "we discovered a way to manipulate nicastrin to either increase or decrease the production of the harmful amyloid beta-peptide. This could lead to new treatments that will target nicastrin to prevent the overproduction of this neurotoxic protein."
"Nicastrin is clearly a very important component of the cellular machinery underlying Alzheimer's and has several features which suggest that it might be used as a target for the development of new drugs for this disease," said co-author Dr. Paul Fraser of the CRND.
It is not yet clear, St. George-Hyslop said, whether genetic variation in nicastrin is associated with an inherited susceptibility to Alzheimer's disease. In Canada, more than 200,000 people over age 65 have Alzheimer's disease and the Alzheimer Society of Canada estimates that more than 750,000 Canadians will have the disease and related dementias in 30 years. St. George-Hyslop and his research team received international acclaim in 1995 for the discovery of the presenilin genes responsible for the most severe forms of early-onset Alzheimer's. He is the recipient of the Medical Research Council's prestigious Michael Smith Award and was named to Maclean's magazine's 1998 Honor Roll.
Funding was provided by the Canadian Institutes of Health Research, the Alzheimer Society of Ontario, the Howard Hughes Medical Institute, and other international agencies.
Victoria Hadden, U of T Public Affairs, (416) 978-5948
Megan Easton, U of T Public Affairs, (416) 978-5949
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