New transgenic mouse likely to advance Alzheimer's disease research

November 23, 1999

A new strain of mice develops, with age, damaging tangles of a normal protein called tau in neurons of the spinal cord, brain stem, and brain. Similar aggregations of the filamentous protein are a key feature in a number of devastating age-related neurological disorders, including Alzheimer's disease. In Alzheimer's disease, for example, the tau tangles and plaques of another protein called beta amyloid in certain neurons of the brain are regarded as the two signature signs of the disease.

The new mouse, which incorporates and overexpresses a human gene coding for the tau protein, is expected to enable scientists to make major strides in understanding the role of tau tangles in this important group of neurodegenerative diseases, referred to collectively as tauopathies. A report describing the mouse, developed by researchers at the University of Pennsylvania Medical Center, appears in the November 24 issue of Neuron.

"The mouse we have developed is the first true animal model for a family of diseases known as tauopathies, the most well-known of which is Alzheimer's disease," says Virginia M.-Y. Lee, PhD, senior author on the study, codirector of the Center for Neurodegenerative Disease Research, and the John H. Ware 3d Professor of Alzheimer's Research in the department of pathology and laboratory medicine. "This mouse isn't, in and of itself, a complete model for Alzheimer's disease, but it should help us better to understand the crucial role that tau tangles play in the progression of that disease, as well as a number of other debilitating neurodegenerative diseases."

Efforts are now under way at Penn to cross the tau mouse with an existing strain of mice that develops beta amyloid plaques to produce a mouse that would even more closely mimic Alzheimer's disease. Lee says her team also hopes to be able to "knock out," or delete, the mouse version of the tau gene from the mouse DNA, leaving only the human gene, in order to fully "humanize" the strain.

According to Lee, there are several characteristics exhibited by the tau mouse that lead her and her colleagues to believe it will prove valuable in research on tauopathies. The first is that the tau tangles develop progressively in the mice as they age. This is an important feature, because the most significant single risk factor for Alzheimer's disease and the other tauopathies is age. The mice also exhibit clinical symptoms of disease that suggest impairment of their motor neurons, symptoms similar to those seen in tauopathies other than Alzheimer's disease. This contrasts with the existing beta amyloid mouse, for example, which demonstrates little or nothing in the way of clinical manifestations and no tau tangles, thus limiting its usefulness to researchers.

One hope that scientists have for the new mouse is that it will help define the specific roles played by tau and beta amyloid in Alzheimer's disease. For many years, the majority of researchers investigating this disease have focused on the beta amyloid plaques. Only a minority thought that the tau tangles might be centrally implicated in disease progression. Recent discoveries, however, including several concerning a group of frontal- and temporal-lobe dementias linked to mutant forms of the tau gene on chromosome 17, have begun to suggest that tau studies should be given greater prominence. The tau mouse should aid in answering questions about the relative roles of the two main pathological markers of Alzheimer's disease.

"Tau has not been as highly regarded a player as beta amyloid in the mechanisms of brain degeneration associated with Alzheimer's disease," says John Q. Trojanowski, MD, PhD, a coauthor on the study, codirector with Lee of the Center for Neurodegenerative Disease Research, and a professor of pathology and laboratory medicine. "Some of us, however, have long believed that tau may be directly responsible for the death of neurons in that and other tauopathies. With this new strain of mice, we should be able to shed new light in this area."

There are some noteworthy differences between the tau tangles in the new mouse and those seen in human diseases. One difference is that the tau tangles seen in Alzheimer's disease and other tauopathies take the form of twisted pairs of tau filaments. In the mice, the tangles are composed of relatively straight single filaments of tau. Also, each tauopathy is characterized by tangles that form in particular neurons. In the tau mouse, tangles are seen in the spinal cord, brain stem, and brain, with the greatest aggregations in the spinal cord. This resembles the tau tangle localization seen in several important diseases, including amyotrophic lateral sclerosis/parkinsonism-dementia complex, progressive supranuclear palsy, and the group of hereditary dementias caused by mutations in the tau gene. It differs, however, from that seen in Alzheimer's disease, where the tangles and beta amyloid plaques appear primarily in cortical neurons involved in memory and cognition.

Alzheimer's disease is a progressive, degenerative disease that attacks the brain and results in impaired memory, thinking and behavior, according to the Alzheimer's Association. It was first described by Dr. Alois Alzheimer in 1906. Approximately 4 million Americans have Alzheimer's disease today, and it is estimated that 14 million will have Alzheimer's by the middle of the next century unless a cure or prevention is found.

The lead author on the study is Takeshi Ishihara, MD, PhD. Other Penn coauthors, with Lee and Trojanowski, are Ming Hong, MD, PhD, Bin Zhang, MD, PhD, and Yasushi Nakagawa, MD. Michael K. Lee, PhD, at The Johns Hopkins School of Medicine, is also a coauthor. The research was supported primarily by grants from the National Institute on Aging, one of the National Institutes of Health.
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The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation - $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the largest absolute growth in funding for research and training among all 125 medical schools in the country since 1991. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page ( http://www.med.upenn.edu ), to EurekAlert! ( http://www.eurekalert.org ), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news service Newswise ( http://www.newswise.com ).

University of Pennsylvania School of Medicine

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