Scientists engineer mice to mimic Alzheimer's therapy

November 16, 2005

GAINESVILLE, Fla. - Researchers with the University of Florida and the California Institute of Technology have developed a new strain of genetically modified mice that allow scientists to examine the potential usefulness of new therapies for Alzheimer's disease.

The development, reported Nov. 15 in the international open-access medical journal PloS Medicine, has helped scientists evaluate the brain's ability to repair one of Alzheimer's hallmark lesions, senile plaque.

These plaques occur when enzymes - proteins that cause or speed up chemical reactions - create peptide fragments called beta amyloid, also known as Abeta. The fragments clump together to form senile plaques, clogging the spaces between cells and damaging parts of the brain used for memory and decision-making.

The mice were genetically engineered by scientists to respond to a type of therapy designed to lower production of Abeta by inhibiting the enzymes responsible for peptide release.

"We can stop the disease from getting worse in these mice, but we can't reverse it," said David Borchelt, Ph.D., a professor of neuroscience at the McKnight Brain Institute of the University of Florida. "Although it is possible that human brains repair damage better than mouse brains, the study suggests that it may be difficult to repair lesions once they've formed."

The need to recognize and treat Alzheimer's patients at the first signs of impairment will be important to the success of potential treatments, said Joanna Jankowsky, Ph.D., a biologist at the California Institute of Technology and first author of the paper.

"The popular expectation was once the peptide accumulating into the plaques went away, the plaque itself would dissolve," Jankowsky said. "But it may be similar to coronary artery disease - once plaques start to occlude your arteries, it's not clear that stopping the contribution to growth will make the occlusion break up and go away."

Alzheimer's disease is a form of dementia, a brain disorder that trips up the thoughts, memory and language skills of about 4.5 million Americans. It is not a normal outcome of aging, but the disease affects about 5 percent of men and women ages 65 to 74, according to the National Institute on Aging. Nearly half of people 85 and older may have it.

Drugs collectively known as secretase inhibitors are currently in development and are based on the theory that lowering production of Abeta could halt progression of disease and perhaps reverse symptoms.

In the first experiments to test the idea in a mouse model, scientists engineered 25 mice to carry two artificial genes, one designed to continuously produce Abeta in their brains and the other to turn off Abeta production. The "off switch" was triggered when the antibiotic tetracycline was added to the animals' food.

With Abeta production in full swing, the brains of mice at 6 months of age were filled with plaques. When the researchers switched the system off, they found the existing plaques did not grow or spread, but they did not go away, either.

"Early treatment will be important to prevent plaque from forming," said Borchelt. "It's likely enzyme inhibitors will work best at the first sign of mild cognitive impairment, when people are first starting to have memory problems in early stages of Alzheimer's disease."
Scientists from the Johns Hopkins School of Medicine, the Mayo Clinic Jacksonville and the National Cancer Institute made major contributions to the research, Borchelt said.

University of Florida

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