Gamma-secretase modulators: with respect to Alzheimer's

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A new class of drugs called gamma-secretase modulators work to reduce the buildup of toxic proteins in the brains of people with Alzheimer’s disease, giving doctors hope that these medications may offer effective new treatments for the devastating brain ailment. Results of advanced-stage testing of one of these drugs, called Flurizan, failed to show any benefit, though this unfortunate failure does not signal that other drugs, based on the same principle – called gamma-secretase modulation -- will fail.

Researchers at the Mayo Clinic report that gamma-secretase modulators work to reduce the production of long pieces of a protein called beta-amyloid that builds up in the brains of those with the disease. These drugs also appear to promote the production of shorter forms of beta-amyloid that may inhibit the longer forms from sticking together and forming brain-damaging clumps. Doctors have long known that beta-amyloid builds up in the brains of people with Alzheimer’s disease. But scientists still don’t know exactly why or how this occurs, and how it may lead to the onset of memory loss and dementia.

Beta-amyloid by itself it not necessarily bad. It is formed from a larger protein called amyloid precursor protein, or APP, that can be snipped into shorter segments by proteins called enzymes. One of these enzymes is called gamma secretase. Gamma secretase acts on a fragment of APP, shearing it like a pair of molecular scissors into smaller fragments of beta-amyloid of varying length.

One resulting form of beta-amyloid, consisting of 42 protein building blocks called amino acids, appears to be particularly toxic to the brain. This 42-amino acid form of beta-amyloid is the main form that builds up in the brains of those with Alzheimer’s disease to form plaques. A hallmark of Alzheimer's is the formation of these plaques, which are believed to damage neurons in complex ways that are not yet fully understood. But beta-amyloid also exists in shorter forms, like the 38- and 40-amino acid segments that appear to be less harmful. These shorter segments may even be beneficial, helping to prevent the longer, and toxic, 42-amino acid form from sticking together to form plaques.

The new drugs, the gamma secretase modulators, are believed to act on APP, rather than the gamma secretase enzyme directly. As a result, when gamma secretase shears the larger APP protein, it tends to form shorter snippets of nontoxic beta-amyloid. At the same time, less of the toxic form of beta-amyloid is produced.

"So, as these compounds lower the amount of the bad, longer sticky beta-amyloid peptides in the brain, they increase the quantity of shorter beta-amyloid peptides that may protect against development of Alzheimer's disease," said the study’s senior author, Todd Golde, M.D., Ph.D., Chair of the Department of Neuroscience at the Mayo Clinic in Jacksonville. "In a very general sense the action of these gamma secretase modulators on beta-amyloid 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," Dr. Golde said.

There is also some evidence that the gamma secretase modulators actually stick to the toxic beta-amyloid already in the brain, keeping it from clumping together. "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 beta-amyloid, may block aggregation of beta-amyloid, and increase production of shorter beta-amyloid peptides that may in turn inhibit beta-amyloid aggregation," said the study's lead investigator, Thomas Kukar, Ph.D. Because these experimental drugs lower levels of toxic beta-amyloid, they are sometimes also referred to as selective amyloid lowering agents, or SALAs. ...http://www.alzinfo.org

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