USC researchers link muscle disease to enzyme associated with"Alzheimer protein"

Researchers from the Keck School of Medicine of the University of Southern California and their colleagues have found that two enzymes involved in the production of amyloid-ß protein—the protein that makes up the plaques found in the brains of Alzheimer patients—are increased inside the muscle cells of patients with the most common, progressive muscle disease of older people, in which amyloid-ß is also increased. The finding has implications for developing treatments for the muscle disease—called inclusion-body myositis or IBM—and, possibly, for Alzheimer disease as well.

The study was published in the December 8 issue of The Lancet.

BACE1 and BACE2 are enzymes that selectively snip the amyloid precursor protein to create the presumably toxic amyloid-ß; they are found in normal tissues at very low levels. But, until now, they had not been shown to be increased in any diseased tissue. "We have found an increase at the protein level of these two enzymes for the first time ever in a human disease," explains the paper’s principal investigator, Valerie Askanas, M.D., Ph.D., professor of neurology and pathology at the Keck School and co-director of the USC Neuromuscular Center at Good Samaritan Hospital in Los Angeles.

IBM is a crippling disease usually found in people over age 50, in which muscle fibers develop inflammation and begin to atrophy—but in which the brain is spared and patients retain their full intellect. "Patients with IBM become very frustrated because they begin falling suddenly, can’t grip things and—with progression—can’t get up and walk," says W. King Engel, M.D., Keck School professor of neurology and pathology, director of the USC Neuromuscular Center and a co-author on the paper. "One of my patients is a carpenter who now can’t hammer because he’s afraid the hammer will fly out of his hands. This is a very insidious, progressive muscle disease."

The discovery of the increase in the two BACE enzymes, notes Askanas, means that treatment for this disease may not be as out-of-reach as it has been in the past. "If factors can be found that can decrease the enzyme, then hopefully amyloid-ß protein would no longer be produced in toxic amounts."

Of course, this could also be useful to the millions of aging Americans who have or will develop Alzheimer disease. Not only are the pathogenic pathways of the two diseases similar, but the muscle cells that are affected in IBM patients are fairly easy to culture and investigate.

"IBM muscle is a fantastic model that can be used to easily study amyloid-ß accumulation, as compared to the brain," notes Askanas, who recently received a merit-award grant from the National Institute of Aging at the National Institutes of Health to study IBM and its relationship to Alzheimer disease. "You can’t take brain cells from Alzheimer patients and manipulate them to see what happens when you decrease these enzymes. But you can do that with IBM—we can take fresh muscle biopsies, culture them and generate the affected muscle cells. The muscle cells in culture express BACE and are a very good living model of the disease in IBM patients. This makes it so much easier to experimentally modulate the amount of BACE in the tissues actually affected—to upregulate it, to downregulate it, to do genetic engineering—to look for potentially therapeutic maneuvers that will lessen or stop the disease process."

And that is exactly what Askanas and her colleagues are planning to do. In fact, they have already collected data showing that cholesterol—for reasons as yet unknown—may increase production of the unwelcome amyloid-ß protein in human muscle culture, and that cholesterol is found deposited in the same places as the small amyloid-ß protein plaques inside IBM degenerating muscle fibers. "So there is definitely a correlation between cholesterol and amyloid-ß deposition," notes Askanas. "That may be relevant not only to IBM—other researchers have reported that persons who are treated with cholesterol-lowering drugs have a much lower incidence of Alzheimer disease. Now we are going to set up a study to treat IBM cultured muscle with cholesterol and see what happens to BACE."

"Patients always want to know the bottom line," says Engel. "Is there a new treatment? Not yet. But we can’t develop a new treatment until we better understand the steps of pathogenesis causing muscle-fiber degeneration. This paper will play an important role in clarifying those steps. All of these things Dr. Askanas and her colleagues are doing are bringing us closer to the eureka point for IBM and, perhaps, for Alzheimer disease."

Gaetano Vattemi, W. King Engel, Janis McFerrin, Joseph D. Buxbaum, Lucia Pastorino, Valerie Askanas. "Presence of BACE1 and BACE2 in muscle fibers of patients with sporadic inclusion-body myositis." The Lancet. Vol. 358, No. 9297, pp. 1962-1964, 8 December 2001.

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