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Breakthrough Discovery Offers Research Hope for Form of Myositis and Possibly Alzheimer's Disease

Irvine, Calif., April 22, 2002 -- A UC Irvine research team has derived the first animal model that exhibits the pathological and behavioral symptoms of inclusion body myositis, the most common degenerative muscle disease among the elderly. The ability to study this form of myositis in live tissue may lead to significant research breakthroughs on this poorly understood and presently incurable ailment.

The effort, led by UCI neurobiologists Frank LaFerla and Michael Sugarman, also holds promise for further advances in research on Alzheimer's disease, the leading cause of dementia in the United States, which shares similar molecular processes with inclusion body myositis. The findings appear in the April 23, 2002, issue of Proceedings of the National Academy of Sciences.

"These mice are valuable because they allow us to evaluate the therapeutic compounds that can halt or reverse the disease, something that previously could not be done," said LaFerla, associate professor of neurobiology and behavior. "Also, because myositis is so closely linked with Alzheimer's disease, this mouse model presents a great opportunity to study the molecular mechanisms that are common to both degenerative disorders in living tissue."

The UCI research focuses on inclusion body myositis, a form of the disease that causes damage to muscle fibers and ultimately leads to loss of muscle tissue, particularly in the limbs. Inclusion body myositis is a relatively new disorder that was first recognized in the early 1970s. It has been historically misdiagnosed, so it is difficult to determine the exact number of affected individuals, although it is regarded as the most common degenerative muscle disease in older Americans.

A small protein called beta-amyloid accumulates pathologically in both Alzheimer's disease and inclusion body myositis. What triggers its accumulation is unclear, although it is well-established that beta-amyloid is derived from a larger parental entity called the beta-amyloid precursor protein. LaFerla and Sugarman created genetically modified mice that produced large quantities of the beta-amyloid precursor molecule selectively in skeletal muscle cells. These researchers showed that abnormally high levels of this protein cause degeneration of muscle tissue leading to the motor-behavioral difficulties associated with inclusion body myositis.

In Alzheimer's disease, beta-amyloid excesses lead to the brain plaques that are thought to cause neural cell death. This study further strengthens the connection to Alzheimer's disease by showing that over-production of this protein can have pathological consequences in muscle as well as the brain.

The UCI researchers achieved this excess of the beta-amyloid precursor protein by cloning it in front of the DNA-control elements of the muscle creatine kinase gene, which was then subsequently injected into mice embryos. Using these gene elements allowed the human beta-amyloid precursor protein, from which beta-amyloid is derived, to be selectively overproduced in skeletal muscle of the mice. The team created two models of mice--one which expresses large amounts of the human protein, which led to more rapid and severe forms of myositis, and one expressing lesser amounts of the human protein, which exhibited a less virulent form of the disease.

In tests, LaFerla and Sugarman found that at 10 months, their transgenic mice began to show deficits in muscle performance, mirroring the age-related aspect of the human condition. Muscle biopsies revealed the pathological features of inclusion body myositis, such as muscle degeneration and inflammation, which is consistent with how the disease progresses in human muscle.

With their mouse model, LaFerla and his team are continuing their myositis research, testing whether exercise can delay the disease's onset, whether muscle injury makes it occur sooner or more severely, and whether enzyme inhibitor drugs that are being used in Alzheimer's research can control beta-amyloid amounts.

"These mouse models are opening up exciting new areas of research," LaFerla said. "Much of our understanding about inclusion body myositis has emerged from studying Alzheimer's disease, but there's no reason to believe that what we learn about myositis cannot be applied to Alzheimer's disease."

The National Institute of Aging supported the research, which is covered by a provisional patent. Assisting LaFerla and Sugarman in the study were Tritia Yamasaki, Salvatore Oddo, Julio Echegoyen, Mehrdad Jannatipour and Malcolm Leissring of UCI, and M. Paul Murphy and Todd Golde at the Mayo Clinic in Jacksonville, Fla.


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