Alzheimer's in a Petri Dish Could Revolutionize Research

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An elderly man holds a portrait of Laurel and Hardy during a memory activity at the Cuidem La Memoria elderly home, which specializes in Alzheimer patients, on August 2, 2012, in Barcelona, Spain. David Ramos/Getty

Researchers have succeeded in growing neurons in a lab that replicate the course of Alzheimer's disease, according to new research published online Sunday in the journal Nature. In one fell swoop, they have proved a 30-year-old hypothesis and created a system that makes testing Alzheimer's drugs faster, cheaper and more relevant.

"It is a giant step forward for the field," Dr. P. Murali Doraiswamy, an Alzheimer's researcher at Duke University, told The New York Times. Dr. Sam Gandy of New York's Icahn School of Medicine at Mount Sinai agreed, telling the Times that the new discovery is "a real game changer" and "a paradigm shifter."

The Alzheimer's Association estimates 5.2 million people are living with Alzheimer's in the U.S. in 2014, with 500,000 seniors dying each year from the disease, a type of dementia that causes problems with memory, thinking and behavior and gradually worsens over time. Alzheimer's deaths increased 68 percent between 2000 and 2010. In 2014, the cost to American society of caring for those afflicted is an estimated $214 billion. Though there are treatments available to ameliorate behavioral and cognitive symptoms, there is no cure yet for the disease.

Dr. George Glenner first identified the substance that formed around Alzheimer's patients' neurons as a protein, called beta-amyloid, in 1984 at the University of California, San Diego. Since then, the "amyloid hypothesis"—that these amyloid plaques start the domino effect of Alzheimer's, causing the telltale neuron tangles, brain inflammation and cell death that lead to dementia—has been on the table, occasionally doubted but neither proved nor dismissed.

"For 30 years it's been conjecture, it's been debatable," Rudolph Tanzi, director of the Massachusetts General Hospital Genetics and Aging Research Unit and Kennedy Professor of Child Neurology and Mental Retardation at Harvard Medical School, tells Newsweek. But now, three decades later, a research team led by Tanzi has unequivocally shown that amyloid leads to the iconic tangles Dr. Alois Alzheimer first described in 1906, and thus to the symptoms of the disease.

Alzheimer's in a dish

The key to these new findings came in the form of a gel-like substance in which Tanzi and his team could grow neurons and introduce Alzheimer's mutations to simulate the disease as it occurs in the human brain.

For years researchers have used mice as imperfect models on which to test theories and drugs, Tanzi tells Newsweek, despite the fact that the results are not always physiologically relevant to humans. For example, even when mice had amyloid plaques, an accumulation of the protein and the initial sign of Alzheimer's, they never developed tangles, so scientists could not replicate the kind of process human brains showed. Often, Tanzi says, drugs tested successfully on mice did not work on people. Scientists have also tried to grow neurons in liquid, he says, but this too has failed.

"The lack of a viable model for Alzheimer's has been the Achilles' heel of the field," Doraiswamy told The New York Times.

Tanzi's co-senior author on the paper, Genetics and Aging Research Unit investigator Doo Yeon Kim, suggested using a gel-based three-dimensional culture system instead to mimic the brain environment and allow neurons, which they made from stem cells, to form networks as they do in the brain. After all, "the brain's not made of liquid," Tanzi says, it's "like three pounds of Jell-O." The cultures, he says, look like "mini spherical brains."

The team then introduced Alzheimer's gene mutations, which Tanzi and others had previously discovered, and waited. Within six weeks, there were full-blown plaques, or amyloid deposits, Tanzi says. Two to four weeks later, the neurons had formed tangles.

"One of the biggest questions since [Glenner's discovery] has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons," Tanzi says in a press release about the Nature study. The previous reigning paradigm, Tanzi says, involved a whole "black box" of events caused by amyloid—including inflammation, oxidative stress and more—that eventually led to tangles and cell death. But the new study shows it's simpler: "In this new system that we call 'Alzheimer's-in-a-dish,' we've been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death."

In other words, the researchers have proved a direct link while creating a model that can be used to test myriad drugs within a few months rather than the year, and major expense, it takes to test on mice.

"That's why so many in the field are excited," Tanzi says. "It's been a dream to have a simple system."

The New England-based researchers also identified an enzyme called GSK3-beta, which is activated by the amyloid and causes the tangles. They proved that they could not only prevent the accumulation of amyloid to avoid tangles but could also block the enzyme once plaques had already appeared, to prevent tangles from forming. Inhibition of the enzyme could be a target for new drugs, according to the press release.

Next steps

Tanzi and his team have already worked on two drugs to prevent the amyloid accumulation, one of which is in clinical trials in Australia, while the other has just been approved for clinical trials by the Food and Drug Administration, he says. But those are just the beginning.

"We're going to go crazy, use this system to screen as many drugs as we can," says Tanzi. He and his team have already begun raising funds to test every single one of the 1,200 compounds currently approved by the FDA, he says, and 5,000 or 6,000 more that have passed phase 1 trials for safety but have yet to be approved.

The caveat, he says, is that "this system recapitulates the earliest events in the disease, [and patients] would have to use any drugs to come out of this system early on." Even if they succeeded in finding drugs to stem the amyloid and tangles, researchers would still need to find additional drugs to treat patients in later stages, who also show inflammation. Tanzi's lab is building on research from last year to develop equivalent three-dimensional systems for brains that exhibit inflammation.

"The bottom line is in this disease you're going to need as many shots on goal," Tanzi tells Newsweek. "The more the better."

Alzheimer's in a Petri Dish Could Revolutionize Research | Tech & Science
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