Visualizing Alzheimer’s disease

Imaging damaged brain cells in living mice provides Alzheimer’s clues

Using recently developed techniques for imaging individual cells in living animals, a team led by researchers at Washington University School of Medicine in St. Louis has watched as Alzheimer’s-like brain plaques damage mouse brain cells.

The results will be presented at 9 a.m. CT on Wednesday, Nov. 12, at the 33rd Annual Meeting of the Society for Neuroscience in New Orleans.

“This work is very exciting,” says principal investigator David M. Holtzman, M.D. “We’ve been able to visualize damaged nerve connections in living animals and follow them over time in the same animal. Our next step is to determine whether such damage is reversible.”

Holtzman is the Andrew B. and Gretchen P. Jones Professor of Neurology and head of the Department of Neurology, the Charlotte and Paul Hagemann Professor of Neurology and a professor of molecular biology and pharmacology. The first author is Robert P. Brendza, Ph.D., research instructor in neurology.

The study was conducted in collaboration with Brian Bacskai, Ph.D., investigator at Massachusetts General Institute for Neurodegenerative Disorders and an assistant professor of neurology at Harvard Medical School; and Bradley Hyman, M.D., Ph.D., director of the Alzheimer’s Unit at the Massachusetts General Institute for Neurodegenerative Disorders; and John B. Penney Jr. Professor of Neurology at Harvard Medical School; William E. Klunk, M.D., Ph.D., director of psychiatry of the Alzheimer’s Disease Research Center at the University of Pittsburgh; and Kelly Bales, senior biologist, and Steven Paul, M.D., executive vice president for science and technology at Eli Lilly and Co.

In the 1990s, biologists discovered the protein that makes certain jellyfish luminescent also could be used to generate fluorescent cells in other species. By shining light on a living mouse engineered to contain these proteins, researchers can watch cellular activity over time using a multiphoton microscope, a sophisticated new microscope technique.

Holtzman’s team used this technique to examine the brains of mice that develop plaques similar to those characteristic of Alzheimer’s disease. The mice also were engineered to have a subset of brain cells, or neurons, that express yellow fluorescent protein. Using this model, they observed neurons becoming increasingly disrupted by brain plaques over time.

“We plan to use this system to further examine the process of nerve cell damage and degeneration,” Holtzman says. “This line of research should provide new insight into the underlying processes involved in the development of Alzheimer’s disease and help us determine whether the proteins that accumulate as brain plaques are a useful and feasible target for Alzheimer’s therapies.”

Brendza RP, Bacskai BJ, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DH. Imaging dystrophy in vivo in fluorescent PDAPP transgenic mice. Society for Neuroscience 33rd Annual Meeting. Nov. 12, 2003.

Funding from the National Institutes of Health, the Alzheimer’s Association and Eli Lilly and Company supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.