Potential Found in a New Approach to Alzheimer's
A potentially promising approach to treating Alzheimer’s disease has been developed by researchers studying sirtuin, a protein thought capable of extending lifespan in laboratory animals.
Using mice prone to developing Alzheimer’s, the researchers showed that activating sirtuin suppressed the disease and that destroying sirtuin made it much worse.
The finding was made by Gizem Donmez, Leonard Guarente and colleagues at the Massachusetts Institute of Technology, who say it raises the hope of treating Alzheimer’s, and possibly other neurodegenerative diseases like Parkinson’s and Huntington’s, with drugs that activate sirtuin.
Researchers not involved in the study agreed. “We think it is a scientifically compelling story that ties the sirtuins to the biology of Alzheimer’s disease,” said Dr. Dennis J. Selkoe, an Alzheimer’s expert at Harvard Medical School. But the therapeutic implications, Dr. Selkoe added, “remain quite up in the air.”
Another expert, Dr. Juan C. Troncoso of Johns Hopkins University School of Medicine, said the finding “opens a very good avenue, but it’s not without a lot of technical challenges.”
Drugs that activate sirtuin already exist, including resveratrol, a minor ingredient of red wine and other foods, and small-molecule chemicals designed to mimic resveratrol. Sirtris, the company that developed the drugs, is testing them against diabetes and other diseases. This generation of drugs does not cross the blood-brain barrier so would not work against Alzheimer’s.
But George P. Vlasuk, Sirtris’s chief executive, said the company had developed other sirtuin-activating chemicals that do reach the brain and are in preclinical trials. “We think it has very significant potential in neurodegenerative diseases,” Dr. Vlasuk said.
Sirtuin has been the subject of intense research in the last few years because it seems to protect the body’s various organs against disease by stepping up maintenance programs. The substance came to light through studies of longevity, particularly the discovery that reduced-calorie diets could lengthen the lifespan of mice by 30 percent. Sirtuin appears to convey much of the beneficial effect of such diets, even though drugs that activate sirtuin have not yet been shown to prolong mice’s lifespan in experiments.
Dr. Guarente, a leading sirtuin researcher, said the protein’s protective power against other diseases made him wonder if it might also help against Alzheimer’s. He obtained mice that tend to develop Alzheimer’s-like symptoms because they are genetically engineered to carry two mutated human genes that cause a buildup of plaque in the brain. The mice were crossed with a strain of mice in which the sirtuin-making gene is particularly active. They were also crossed with a strain in which the sirtuin gene was deleted entirely. Dr. Guarente’s team could thus test the effect of having either more or less sirtuin in the brains of Alzheimer’s-prone mice.
The decline in memory typical of Alzheimer’s “was clearly suppressed” in the Alzheimer’s-prone mice with abundant sirtuin, the M.I.T. group reports in Friday’s issue of Cell, while the mice with Alzheimer’s genes and no sirtuin started to lose memory at a much younger age.
The team found the sirtuin protected the mice’s brains two ways. First, it activated a system called the notch pathway, which protects brain cells against stress. Second, it enhanced an enzyme whose activity avoids the buildup of the plaque characteristic of Alzheimer’s and particularly of a toxic component called A-beta peptide.
Reducing the amount of A-beta peptide is helpful only in Alzheimer’s but turning on the notch pathway could provide general protection for the brain. Activating sirtuin, the M.I.T. researchers conclude, “is a viable strategy to combat Alzheimer’s disease and perhaps other neurodegenerative diseases.”
Dr. Guarente said he was looking into whether extra sirtuin had an effect in mice made vulnerable to Parkinson’s and Huntington’s disease.
Activating the notch pathway with sirtuins “opens a lot of options,” Dr. Troncoso said. “If we can activate the same gene we may provide a tonic for nerve cells under stress, and that may be of use in other diseases such as Huntington’s and Parkinson’s in which the nerve cells degenerate,” he said.
Sirtuin research is a highly active field but one whose ultimate benefit remains to be seen. The sirtuins seem to be powerful players in maintaining the body’s health, but many aspects of their behavior are still unclear.
Also unclear is whether sirtuin’s protective effects can be elicited by drugs instead of by the usual natural stresses, like lack of nourishment. There are continuing disputes as to whether resveratrol activates sirtuin directly or indirectly. Much may depend on a Phase 2 clinical trial of resveratrol with Type 2 diabetes. The results of the trial should be known later in the year, Dr. Vlasuk said in an interview last month.
Should resveratrol prove ineffective, Sirtris has two small-molecule chemical drugs, known as 2104 and 2379, which are also in clinical trials. The chemicals can be given in much smaller doses than resveratrol. There have been no safety issues with any of the drugs, Dr. Vlasuk said, with the possible exception of a multiple myeloma trial, using very high doses of resveratrol, in which several patients developed a symptom common with the disease. The trial ceased new enrollment of patients in May.
The New York Times, July 23, 2010