Researchers at Mayo Clinic, with their national and international collaborators, have discovered how a class of agents now in testing to treat Alzheimer's disease work, and say they may open up an avenue of drug discovery for this disease and others.
In the June 12 issue of Nature, they report that agents known as gamma-secretase modulators (GSM) work to reduce production of long pieces of the amyloid beta protein (Abeta) that readily stick together and form clumps, and increase production of shorter Abeta that can inhibit the longer forms from sticking together.
This is critical because only when Abeta aggregates and accumulates is it harmful and can trigger Alzheimer's disease, the researchers say. "So, as these compounds lower the amount of the bad, longer sticky Abeta peptides in the brain, they increase the quantity of shorter Abeta peptides that may protect against development of Alzheimer's disease," says senior author Todd Golde, M.D., Ph.D., Chair of the Department of Neuroscience at Mayo Clinic in Jacksonville. "In a very general sense the action of these GSM on Abeta might be analogous to some cholesterol lowering drugs that can lower LDL, the bad cholesterol that sticks to your arteries, and can raise HDL, the good cholesterol that sweeps out LDL," he says.
Not only that, GSM agents actually stick to the Abeta already in the brain, keeping it from aggregating. A hallmark of Alzheimer's is formation of "plaques" and other assemblies of Abeta protein in the brain, which are believed to damage neurons in complex ways that are not yet fully understood, researchers say. "Surprisingly, this means that these compounds may do three things that may be beneficial with respect to Alzheimer's disease: they inhibit production of long Abeta, block aggregation of Abeta, and increase production of shorter Abeta peptides that may in turn inhibit Abeta aggregation," says the study's lead investigator, Thomas Kukar, Ph.D. As exciting as these discoveries are, the investigators which number 29 in all and are from four nations - also found that GSMs work in a way that has not been seen before in other drugs. "Most drugs target enzymes, which act on proteins, or cell surface receptors, which proteins bind to," he says. "These agents work on the structure, or substrate, of the protein itself, which had not been believed to be druggable." "This broadens the notion of what drugs can do, and therefore, has wide reaching implication for future drug discovery for many different disorders," Dr. Golde says.
The findings also suggest that GSMs now being tested or in development to treat Alzheimer's may prove to be valuable, the researchers say. One such drug, tarenflurbil (FlurizanTM), is in Phase III clinical trials, and results from the first, a 1,600-patient US study, are expected this summer. Results of a phase II study, published online in April in Lancet Neurology, suggest it provides benefit in patients with mild Alzheimer's, Dr. Golde says. ...http://www.alzinfo.org
posted by Valery Yermalitsky at
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