An obstacle to understanding how Alzheimer's disease develops has been the lack of an accurate animal model for scientific study. Now, scientists in Cleveland report that they have developed novel genetically engineered mice that exhibit pathological characteristics of Alzheimer's disease. These mice will likely provide new insights into the disease and its treatment.
In work to be published in the August issue of the journal Nature Neuroscience, Bruce Lamb, assistant professor of genetics, and colleagues at Case Western Reserve University's School of Medicine and University Hospitals of Cleveland created the lines of mice using yeast artificial chromosomes to transfer pieces of human DNA into mice. The researchers incorporated into the mice entire copies of human genes that result in early-onset Alzheimer's disease in humans.
One gene encodes amyloid precursor protein (APP), the protein that gives rise to the characteristic amyloid deposits (beta-amyloid proteins) that occur in the brains of Alzheimer's disease patients. The other gene encodes presenilin-1 (PS-1), a protein that has been implicated in the biochemical processing of APP.
The researchers found that mice carrying the mutant form of APP developed amyloid deposits similar to those found in patients with Alzheimer's disease. Moreover, mice with two copies of the APP gene, or with both mutant genes, developed even more deposits.
"Higher levels of beta-amyloid protein are vital for the appearance of Alzheimer's disease pathology in mice, similar to what has been observed in humans with the genetic forms of the disease," said Lamb, who is also affiliated with the University Alzheimer Center in Cleveland. "In addition, further elevation of the levels of beta-amyloid accelerates the age of onset of pathological changes observed in the mice."
He said that additional experiments will be necessary to determine the relationship between the pathology observed in these transgenic mice and other characteristic signs of the disease, including neuronal cell loss and deficits in cognitive function.
"But as these mice contain the entire human genes involved in Alzheimer's disease, as opposed to smaller portions of the genes employed by other investigators, they will likely provide unique insights into the mechanism and progression of Alzheimer's disease in humans as well as provide a novel small animal model for testing therapeutics," Lamb said.
Funding supporting the work came from the National Institutes of Health, the American Health Assistance Foundation, and the Bristol-Meyers Squibb Pharmaceutical Research Institute.
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