Mighty mice carry the hope for Alzheimer's cure 'Transgenic' colony created at Hopkins

September 01, 1993|By Jonathan Bor | Jonathan Bor,Staff Writer

Several hundred strong and multiplying all the time, a colony of mice engineered to carry a human gene for Alzheimer's disease could lead scientists to treatments for an affliction that robs people of their ability to think.

Scientists at the Johns Hopkins School of Medicine, who created the "transgenic mice" using a novel technique of genetic engineering, said yesterday that the rodents could show them how the disease evolves in the brain and what might be done to stop it.

The brown rodents, housed in plastic cages that line the shelves of two rooms, are the latest in a string of animals at laboratories around the world that have been genetically manipulated to carry features of human diseases. Notable examples are cystic fibrosis and Duchenne muscular dystrophy.

"We're absolutely dependent on animal models to get to the basis of what's happening with Alzheimer's disease," said Dr. John D. Gearhart, who runs the Hopkins laboratory. "How does it unfold? Can we stop it? Can we ameliorate it?"

Although the first mice were born in January, details of the colony were revealed yesterday in a scientific article appearing in the journal Nature Genetics.

Alzheimer's is a progressive condition in which brain cells degenerate and die, causing people to forget, lose their way and become dependent on others for basic needs. It is a common condition of aging -- rare among people younger than 60 while afflicting about one-third of people over the age of 85.

The Hopkins researchers were careful not to oversell their creatures as "Alzheimer's mice." They do not yet know how many of them -- if any -- will develop the hard plaques that accumulate inside the brains of people afflicted with the disease, let alone the crippling symptoms of forgetfulness and confusion.

Besides looking for the plaques, researchers plan to give learning and memory tests to the animals to see if they exhibit the behavioral symptoms of Alzheimer's. For instance, they will observe whether the mice remember how to get through a maze that they previously learned to navigate.

If they appear afflicted, the mice could prove valuable subjects in the search for helpful drugs.

The oldest mice in the colony are 8 months old. But in the two- to three-year life span of the average mouse, that's a fairly long period of time. It takes just four weeks for a mouse to be weaned off its mother's milk and only one week later, the animal is capable of mating.

With such a fast-ticking biological clock, the colony has already produced its third generation.

While researchers have observed the characteristic plaques in humans, they have not seen them in mice. The Hopkins scientists, however, believe they have predisposed their mice to the disease by giving them the gene to make "amyloid precursor protein" -- a substance that may lie at the root of Alzheimer's disease.

The protein, found on the cell membrane of humans, is thought to be the origin of the plaques that accumulate outside the nerve cells of people afflicted with Alzheimer's. One popular theory holds that the plaques cause brain cells to die, leading to the evolving symptoms of dementia.

Inserting the gene into a mouse embryo was a problem that confounded many scientists who had struggled for years to do it. The gene is a huge and ungainly one, requiring a large and perfectly crafted vehicle that can deliver it intact.

Dr. Bruce T. Lamb, a research fellow, crafted a way of cementing the human gene inside a yeast cell that could then be inserted inside a mouse embryo. The result was a mouse that could pass its human gene onto successive generations of offspring.

So far, the scientists have discovered that the human gene has succeeded in giving mice the "precursor protein." They have not, however, found signs of the plaques, although they speculate that even the oldest mice may be too young to develop them. The Hopkins team is striving to create another line of mice with a defective gene that causes people to develop Alzheimer's early in life. Ultimately, a third line of mice could contain both human genes, a strategy that could increase the odds that a given mouse will have the human disease.

"We really don't want to oversell this, but it's of enormous value have a small animal model that reproduces features of human diseases," said Dr. Donald L. Price, a Hopkins professor of neuropathology who is researching Alzheimer's, Parkinson's, Lou Gehrig's and other neurological diseases.

"We'd have an enormous leg up on understanding the mechanisms as well as the diagnosis and treatment of Alzheimer's."

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