DIMENSIONS Winter 2001

SPOTLIGHT ON RESEARCH: UW RESEARCHER DEVELOPS EXPERIMENTAL MODELS FOR TESTING NEW TREATMENTS FOR ALZHEIMER'S DISEASE

by Cheryl Dawes

Destructive changes in brain tissue produce the devastating memory loss of Alzheimer's disease (AD). UW researcher Dr. Lee-Way Jin studies brain cell and animal models to gain a better understanding of these changes at the cellular and molecular level. His focus is biochemical changes that occur early in the disease and may be susceptible to intervention

Jin, assistant professor of pathology and director of the Neuropathology Core of the ADRC, is currently investigating three models that show various aspects of the progressive damage associated with AD. His research centers on beta-amyloid protein, a major component of the deposits of amyloid, or plaques, that characterize AD.

There is little question that these amyloid deposits somehow damage the brain. Jin seeks to determine just how the deposits form and why they are toxic to brain tissue. Answers to these questions could guide development of therapies to prevent or slow the progression of AD.

Studies of families with inherited AD show that the defects in the genes related to the disease are also related to abnormal beta-amyloid production. This link points to abnormal production of beta-amyloid as a central event in the disease process, explains Jin. However, understanding just how this event leads to the disease is less straightforward. Inherited AD is rare. Most people with AD do not have defects in the genes that are associated with the inherited forms. For most people with AD, abnormal beta-amyloid production is probably the result of the interactions of multiple genes and environmental factors. To sort out those influences, Jin takes several approaches-making genetic modifications, creating changes in environmental factors and applying potential therapeutic interventions.

In one of his models, Jin has genetically manipulated neurons grown in culture so they produce a large amount of beta-amyloid. He found that these cultured nerve cells died over a three-day period, as beta-amyloid accumulated in them. Although the actual cause of death is not clear, Jin, in collaboration with chemist Dr. Duy Hua, discovered a way to stop it. Jin determined that the presence of a tricyclic compound called tricyclic pyrones (TP) prevented cell death that would otherwise occur as beta-amyloid built up. "These TP compounds will be a useful tool to study the mechanism of beta-amyloid neuronal toxicity and may potentially be a therapeutic agent for AD," says Jin.

In another model, Jin is using transgenic mice to examine the relationship between beta-amyloid production and two molecules associated with cholesterol metabolism. Research with this animal model, which has a gene for inherited AD incorporated in its genome, has suggested that cholesterol levels may affect the progression of AD.

These results kindled Jin's interest because two of the molecules involved in cholesterol metabolism--low-density lipoprotein (LDL) receptor and an associated molecule called FE65--are involved in the production of beta-amyloid. By studying mice that lack the ability to produce LDL receptor and FE6, he can look closely at how the missing molecules affect beta-amyloid production. "If these experiments yield significant results, compounds that modify the activity or levels of these two molecules should be designed for therapeutic testing," he says.

Jin's third model is also an animal model. This work involves a different line of transgenic mice that was developed to study beta-amyloid production in skeletal muscle. These mice develop lesions similar to those in a human muscle disease called inclusion body myositis (IBM) and are called IBM mice.

Jin points out that, as with AD, IBM is an age-associated disorder. It is the most common muscle disease in patients over 55 years old, leading to progressive muscle weakness and degeneration. As yet, there is no treatment for IBM.

A major feature of IBM is beta-amyloid deposition and amyloid formation in the degenerating muscle fibers. "The IBM lesions in muscle have striking similarity to AD lesions in the brain," says Jin.

Jin has characterized the muscle lesions in the IBM mice and is now trying to determine what molecular changes might affect development of the lesions. His findings are likely to have implications for more than IBM.

"This is a model of beta-amyloid production in a peripheral organ that is amenable to biopsy studies," Jin says. "In other words, we can sequentially biopsy the skeletal muscles to closely follow the progression of amyloid formation, something we cannot do with brain tissue." The new model could expedite evaluation of drugs aimed at intervening in abnormal beta-amyloid production and amyloid deposition, the prime suspects in AD.


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