Scientists recreated what goes on in the brains of Alzheimer’s patients in a 3D culture dish that could speed development of new drugs for the disease
Researchers have overcome a major barrier in the study of Alzheimer’s that could pave the way for breakthroughs in our understanding of the disease, a new report shows—and that new understanding could, in turn, pave the way for drugs that treat or interrupt the progression of the neurodegenerative condition.
For decades, animals have been the stand-ins for studying human disease, and for good reason. Their shorter lifespans mean they can model human conditions in weeks or months, and their cells can be useful for testing promising new drug treatments.
But they haven’t been so helpful in studying Alzheimer’s disease. Two factors contribute to the neurodegenerative condition — the buildup of sticky plaques of the protein amyloid, and the toxic web of another protein, tau, which strangles healthy nerve cells and leaves behind a tangled mess of dead and dying neurons. Despite attempts by scientists to engineer mice who exhibit both factors, they haven’t been able to generate the tau tangles that contribute to the disease.
Now, Dr. Rudolph Tanzi and Dr. Doo Kim at the Mass General Institute for Neurodegenerative Diseases at Massachusetts General Hospital, have devised a work-around that doesn’t involve animals. They have developed a way to watch the disease progress in a lab dish.
“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,” said Tanzi in a statement.
While autopsies showed evidence of both amyloid and tau in the brain, Alzheimer’s experts have been debating for years which came first — do amyloid plaques trigger the formation of tau tangles, or does the presence of tau cause amyloid to get stickier and bunch together in the brain? Tanzi and his colleagues showed definitively for the first time that amyloid is the first step in the Alzheimer’s process, followed by tau tangles. When he blocked the formation of amyloid in the culture with a known amyloid inhibitor, tau tangles never formed.
The disease-in-a-dish model is an emerging way of understanding conditions that either can’t be recapitulated accurately in animals, or diseases that make it difficult to study and test in human patients. In recent years, for example, scientists have successfully recreated the process behind amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, using stem cells from patients and allowing them to develop into the motor neurons that are affected by the disease. The technique led to a breakthrough in understanding that a certain population of nerve cells known as glial cells poison the motor neurons and impede their normal function. Now experts are focusing on finding ways to control the glial cell activity as possible treatment for ALS.
Tanzi and his team are hoping that something similar will come from their model of Alzheimer’s.
While the genes responsible for the inherited form of Alzheimer’s differ slightly from those involved in the more common form that affects people as they age, the end result — the build up of amyloid plaques and tau tangles — are the same. So now that they can see both the clumps of amyloid and the tau tangles, form, they can start to tease apart the processes that link the two processes together.
That will open the way toward finding drugs or other ways of interrupting the process more quickly than they could working with animals. It took six to eight weeks for the cells in the dish to form plaques and then tangles, compared to a year or so in mice. “We can now screen hundreds of thousands of drugs in this system that recapitulates both plaques and tangles…in a matter of months,” Tanzi said. “This was not possible in mouse models.” The system also makes it possible to test these drug compounds at one-tenth the cost of evaluating them in mice, he said. And that means that finding a way to prevent Alzheimer’s may come both faster and cheaper than scientists had expected.