Researchers find signs of lethal cell division in mouse models for AD

May 09, 2003

For many years now, scientists have relied on genetically engineered mouse models of Alzheimer disease (AD) to chart new course for treatment and diagnosis. The best known (and best studied) of these are lines carrying extra copies of either the beta-amyloid precursor protein gene or the presenilin-1 gene in their genomes. These mutant genes are known to cause early-onset familial AD, an inherited form of the disease. These models have been highly successful in modeling the process of amyloid plaque deposition, the pathological signature of AD, and the mice develop behavioral defects. However, the models have been disappointing in that they fail to mimic the substantial loss of nerve cells normally occurring during the development of dementia in AD.

New work to be presented at the 6th International Conference for Alzheimer's Disease/Parkinson's Disease, May 8 through 12 in Seville, Spain, by researchers from the University Memory and Aging Center and the departments of Neuroscience and Genetics at Case Western Reserve University (CWRU) and University Hospitals of Cleveland (UHC) offers a major new insight into this discrepancy between the human and mouse conditions.

The laboratory of Karl Herrup, Ph.D., has previously reported that the neurons in the susceptible brain regions of AD begin a lethal attempt at cell division before they die. (Mature brain cells are not programmed to divide.) Furthermore, once the lethal cell division begins, the death process itself appears to take up to a year to complete.

Now, Yan Yang, Bruce Lamb, Ph.D., and Herrup of UHC and CWRU have examined the mouse models of AD engineered by Lamb and looked for signs of cell division, or cell cycle events. The team has discovered that, just like their human counterparts, the nerve cells which are at-risk for death in the mouse AD model duplicate their DNA. In other words, they make an attempt at cell division.

"We know that this is a bad decision for an adult nerve cell to make. It almost always dies when it tries to divide," says Herrup. "Finding that the disease process begins in the mouse in the same way that it does in the human means that the mouse model may be much better than we thought at first."

But why don't researchers see signs of neuron death? Yang suggests, "It may be that the mouse simply doesn't live long enough." The average life expectance of a laboratory mouse is a little over two years. If the long time interval between starting cell division and nerve cell death is the same in mouse and human, the death of the mouse at two years may well block any chance researchers would have to see the actual cell death process start.

"Nonetheless, knowing that the underlying mechanism of cell death is the same means that experimental therapies can be tested productively in these model systems," says Herrup.
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Case Western Reserve University

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