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Big Alzheimer's Studies and Tiny Mice at Washington University

Photo by Sean Corcoran

Part 3 of our 5-part series "Desperate for a Cure: The Search for New Alzheimer's Treatments."    

As researchers work to find Alzheimer's treatments, they have a small, furry ally at their disposal -- the mouse.  And at Washington University School of Medicine in St. Louis, they live in a lower level of the school, well below the series of labs upstairs where dozens of researchers are looking for ways to stop Alzheimer's disease.

"You definitely smell the smell of mice housing," said Dr. David Holtzman, the chairman of the neurology department. "And you can see here that we have people who are doing surgery on mice to be able to put different substances in their veins or their arteries.

"Just for my lab, not any other lab, we have 1,200 cages for mice. Each cage averages about 3, which means we have about 3,500 to 4,000 mice that we're studying right now."

If -- or when -- a preventative or cure for Alzheimer's disease is found, these mice -- or ones very similar -- will deserve a lot of the credit. While animals don't naturally get Alzheimer's disease, these mice have been genetically modified to create changes in their brains much like what the human brain experiences when its hobbled by Alzheimer's.

"And since the genes in mice are very very similar to what they are in humans," Holtzman said," you often can mimic disease aspects much better, rapidly."

Washington University researchers were the first to use a technique called microdialysis, to measure the amounts of Alzheimer's-related proteins in the brains of mice.

Proteins are important molecules in our bodies, and some of them are involved in Alzheimer's disease, including amyloid, which globs together into brain plaques. To take measurements of brain fluids, researchers put the mice to sleep, and surgically implant tiny probes and tubes into their brains. Then, the the mice wake up, they walk around, seemingly unaffected, and they live in this space that looks like a large salad bowl.

Credit Sean Corcoran / WCAI
Dr. David Holtzman stands between two rows of freezers, where brain and spinal fluid samples are stored for two of the world's largest and most significant Alzheimer's research projects.

  "What we do," Holtzman said, "is this little apparatus here is hooked up to the head of a mouse, so as the mouse walks around, this bowl will turn with the mouse, so the tubing that goes up into the fraction collector doesn't get tangled."

In a living brain, in real time, researchers, measure things such as if drugs work to clear away Amyloid or limit its production.

"You can assess the blood, you can assess the tissues," he said. "You can't always do that in as easily in a person, for example. You can test things that might be toxic and figure out if their bad or good."

Dr. Neil Buckholtz is the director of the division of Neuroscience at the National Institutes of Health, which funds projects related to transgenic mice, and other science geared towards finding a cure, such as new brain scans and better chemicals to see the disease under microscope. New drugs are needed, as are well-screened volunteers to test them. It's all critical, Buckholtz said, just like the rodents.

"The mice are important because you can put various genes in the mice," he said. "That's how they become what we call transgenic. So you can look at what happens in the brain as these plaques develop, what affects they have. And also use them to basically access whether there are interventions, various kinds of drugs, or other kinds of interventions that may reduce the amount of plaques and the amount of beta amyloid in the brain to give you at least clues into maybe what may be effective for human beings."

When it comes to finding those drugs or interventions, Washington University in St. Louis is one of the nation's most productive Alzheimer's labs in the country, and a top recipient of the NIH's limited research dollars. And much of the money is related to projects associated with this room, where where 20 large freezers hum, each one set at -80 degrees Celsius to keep chilled thousands upon thousands of samples.

"This is the storage room," Holtzman said, "where we store not only samples from animals or cells, but we store all of the cerebral spinal fluid and plasma from our human studies on Alzheimer's disease where we're collecting longitudinal samples in both cognitively normal -- cognitively normal people as they're aging -- as well as people with Alzheimer's disease. And all of the DIAN Network -- -- so Dominantly Inherited Network Samples … -- are stored in these freezers. These are from all over the world -- Australia, Europe, England, US, all of them are here."

DIAN-project researchers track people whose genetics indicate that they'll develop Alzheimer's in their 30s, 40s or 50s. The gene is inherited, so it's called familial alzheimer's, or early-onset. A parent has a 50 percent chance of passing along the genetics for this. If someone tests positive for the gene mutations, they almost always develop symptoms at the same age as their parents. It's very sad. But ironically, to know exactly when a disease will show its symptoms could help researchers find a cure.

Volunteers in the DIAN network test new drug therapies designed to prevent or slowdown the disease. Also stored in this room are samples from what's called the Alzheimer's Prevention Initiative. While DIAN is a world-wide effort, the Alzheimer's Prevention Initiative focusses on a specific group of people living in Colombia.

"They're looking at individuals all who have the same mutation," Holtzman said, "who all came from an initial founder, I think in the 1600s, who had come from Spain and introduced this mutation into the people who were living in the country of Colombia at the time. And now there are thousands of people with this mutation that are being studied, and also being in a treatment trial with a drug called 'Crenezumab'"

There are teams of researchers working on various Alzheimer's projects at Washington University. In Holtzman's case, he began studying the genetics involved in common Alzheimer's, or late-onset, back in the 1980s. In addition to working with patients in the clinic, he's one of the field's most prolific publishers, writing dozens of seminal papers about everything from the genes involved, to new advancements in clearing the Alzheimer's-related proteins from the brain. Holtzman also lost his father to Alzheimer's three years ago.

"It just makes you think about it every day when you're going to work," he said. "It's not like some obscure problem. You really see day to day that it causes someone to be whoever they were, to basically lose their human identity in -- s they were before. Even at the beginning of the disease that you call the very mild stage, he wasn't the same person he was before in terms of his ability and his personality was changing."

Holtzman said he's bewildered by the lack of investment in Alzheimer's disease, especially when considering that recent statistics show if no new therapies are found to delay or prevent it the number of people with Alzheimer's will triple in the next 34 years.