Mayo Magazine

Halting Alzheimer's Disease

Collegial and philanthropic support has helped Jada M. Lewis, Ph.D., create new animal models of human diseases. Pictured with Dr. Lewis are Dennis Dickson, M.D., (center) and Michael Hutton, Ph.D., (left), two of her frequent collaborators.

"We think of each research group as part of a team, but we also think of our patients who participate in research and our benefactors as part of the same team. It's not a purely scientific team; it's something much larger."

– Jada M. Lewis, Ph.D.

New research model shows promise

In July 2005, a research team including Mayo Clinic investigators, made an astonishing discovery: It may be possible to reverse much of the memory loss that occurs with Alzheimer's disease and similar disorders, even in people who are in the later stages of the disease.

Now, scientists throughout the world are rethinking therapies for Alzheimer's disease and other dementias. This shift in thought is the result of a new animal model of dementia created by Mayo scientist, Jada M. Lewis, Ph.D., and her collaborators at both Mayo Clinic and the University of Minnesota.

The new model is a first for neuroscience research. It's a transgenic mouse — one whose genetic makeup is manipulated to contain a human gene — with an additional molecular feature that allows scientists to activate or deactivate the gene's activity with a simple chemical diet. The human gene implanted into these mice is a mutated gene, first identified by Mayo scientist, Michael L. Hutton, Ph.D. The gene causes a tauopathy, which is a type of dementia caused by abnormalities in tau — a naturally occurring protein in the body.

These properties allowed Dr. Lewis and her colleagues to induce dementia to progress to a point that would be considered the disease's late stages and then to turn it off. Much to their surprise, when the disease process was deactivated, the mice regained much of their original cognitive abilities, despite the physical damage the disease had exacted on their brains.

"Our model basically told us that people with tauopathies are likely to benefit from therapeutics at different stages of the disease process, and we really didn't know that until now," Dr. Lewis says. "Our best guess would have been that therapies could work at the earlier stage of the disease or in people who were initially affected. But this gives us hope that we can someday help people in whom the disease is much further along."

This is just one of the many theories that may prove true as a result of this new tool for research, as Dr. Lewis and her colleagues refer to the model. Because the disease process can be activated at will, it allows scientists to investigate tauopathy from many perspectives. For example, in the months ahead, Dr. Lewis plans to use the mice to better understand aging's influence on dementia.

"Everyone will tell you that aging is a risk factor for dementia, but we really don't know if that's true or why it's true," Dr. Lewis says. "We allow these mice to age to different points and then activate the disease process to see if it happens more rapidly in older animals."

This new model is one of several that Dr. Lewis has helped create since coming to Mayo Clinic Jacksonville eight years ago. Describing the importance of her work, she says that her focus is on developing better therapies, and the mouse models are a necessary component of a larger team effort.

"In Alzheimer's disease and related disorders, it's impossible for one scientist or laboratory to answer all of the questions, and so it's important to see each group as part of the larger team of people worldwide who are investigating these diseases," she says. "The way my group contributes to this effort is to make additional tools, to allow scientists to ask questions, to replicate the disease and to be able to manipulate the disease."

They're highly sought-after tools, as well. An earlier model that Dr. Lewis created was requested by 80 academic laboratories and licensed to several pharmaceutical companies. She fully expects the new, inducible model to be distributed to up to 200 academic labs.

Assistance from philanthropy and Mayo colleagues

Dr. Lewis' most recent successes have roots in events that occurred shortly after her arrival at Mayo Clinic Jacksonville, as a postdoctoral student in Dr. Hutton's laboratory. During Dr. Lewis' first week, Dr. Hutton made his groundbreaking discovery, identifying the first genetic mutation in tau that causes tauopathy.

For disease modelers like Dr. Lewis, these genetic discoveries are similar to receiving blueprints for designing new animal models of diseases. Armed with this information, they can use genetic techniques to create a strain of mice that carry the human, disease-causing gene, have similar brain pathology to what is seen in dementia patients and exhibit impairments consistent with dementia. In her efforts to create these models, Dr. Lewis has an enthusiastic collaborator in Dennis Dickson, M.D., a renowned Mayo neuropathologist.

"Just the general bank of knowledge represented by our researchers here is amazing," Dr. Lewis says. "In addition to their expertise, they're very supportive. You can always walk into somebody's lab and say 'I need to learn how to do this,' or 'Will this work?'"

Within a year of her arrival, Dr. Lewis was part of a team that successfully designed the first transgenic animal model of tauopathy. At the time, she had already submitted a proposal for philanthropic support from the John Douglas French Foundation, from which she ultimately received a two-year grant.

That, in turn, allowed her to make progress studying the new animal model and identifying a possible therapy for one type of tauopathy. With these results in hand, she competed successfully for long-term support from the National Institutes of Neurological Disorders and Stroke (NINDS), which allowed her to establish her own laboratory.

"The support of the John Douglas French Foundation, as well as other philanthropy to Mayo, allowed me to develop a research plan that put me in a position of applying for NINDS funding," Dr. Lewis says.