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ALZHEIMER'S BREAKTHROUGH


LONDON- The successful creation of a new transgenic mouse carrying a gene for human Alzheimer's disease should offer researchers an important new research tool in the search for useful treatments for what is currently an incurable disease.

Many researchers consider the deposition of a starch-like protein called beta- amyloid in the brains of Alzheimer's patients to be the key to understanding the disease. Genetic researchers have identified pathogenic mutations in a gene which encodes the b-amyloid precursor protein (APP). Alterations in this gene lead to altered processing of APP and increased deposition of the potentially pathogenic beta-amyloid deposits.

The researchers took a new approach to a problem that has challenged science for years, the development of a transgenic Alzheimer's mouse. The investigators created a construct composed of the full length human APP complementary DNA with the APP mutation under the control of a factor called platelet-derived growth factor (PDGF) promoter. They inserted selected introns from the APP gene important for the splicing of the gene product into this construct. In other words, they constructed a combination of complementary DNA and a genomic construct. The DNA element helps activate the gene in the parts of the brain affected by Alzheimer's disease, the hippocampus and the cerebral cortex. This gene construct was then inserted into mouse embryos using microinjection techniques.

No neurological changes were seen in the mice in the first six months of life. However, between six and nine months the transgenic animals developed many of the characteristics of the brains of patients with Alzheimer's disease. These included the deposition of beta-amyloid plaque, neuritic damage and reduction in synapse density. As the animals aged the amyloid plaque deposits continued to increase in size, resembling human pathology. Non transgenic littermates showed none of these changes.

The next step will be to breed large number of the mice and observe them for signs of cognitive changes associated with Alzheimer's including memory loss. The researchers will also want to determine what elements of the construct allowed the experiment to succeed- the promoter, the use of introns and/or the mutations.

Alzheimer's research has been limited by the lack of a reliable animal model. The development of the Alzheimer's mouse will help researchers understand the pathology of the disease. First, the creation these transgenic animals may finally answer the question of whether the amyloid plaques do cause Alzheimer's disease. Second, the transgenic mice in the current experiment developed most of the pathologic changes seen in human brains with the exception of neurofibrillary tangles. This observation alone may cause a reconsideration of the pathogenesis of the disease, suggesting that these tangles are a result of a destructive neurological process rather than a cause.

The new transgenic mouse should also speed the development of drugs for treating Alzheimer's in humans. Researchers will be able to screen large numbers of drugs in the animal model before proceeding to human trials with any promising agents.

Alzheimer's disease is the fourth leading cause of death in the developed world, after heart disease, cancer, and stroke. Alzheimer's disease strikes some four million Americans, at a cost to the nation of $100 billion. The disease is named for Alois Alzheimer, the German neurologist who first described the pathology of the disease nearly 100 years ago.

The details of the Alzheimer's mouse research can be found in Nature, v.373, 2/9/95, Games et al. pp. 523-537 and pp. 476-77.


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