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Alzheimer’s-in-a-Dish Provides Novel Model for Disease, Will Enable Rapid Drug Discovery

05/Feb/2015 In a major advance for understanding and treating Alzheimer’s disease, MIND researchers Doo Yeon Kim, PhD and Rudolph Tanzi, PhD have for the first time replicated in the lab the brain lesions characteristic of the disease. Using human stem cells and a novel 3D culture system, the duo created for the first time a faithful reproduction of the plaques and tangles that mark this feared and common form of dementia. Their work answers some long-standing questions about how Alzheimer’s disease arises, and promises to greatly accelerate the discovery of new treatments for the disease. 

“This gives us a way to mimic the disease and model it,” said Tanzi, who is the director of the MGH Genetics and Aging Research Unit and vice-chair of Neurology Research, where Kim is an assistant professor. “And having the model so conveniently in a dish will make drug discovery 10 to 100 times faster and 10 to 100 times cheaper.”

Alzheimer’s disease is marked by twin pathologies that show up under the microscope during autopsy. Cottony clumps of toxic amyloid protein appear as senile plaques, while coalesced tau proteins show up as spider-like tangles. It is the tangles that kill cells, but debate has raged for thirty years in the Alzheimer’s research community as to what initiates the deadly cascade—the amyloid, the tangles, or something else.

Tanzi’s own work on the genetics of Alzheimer’s disease left him firmly convinced that amyloid is the root cause. Genetic mutations that boost amyloid production trigger early Alzheimer’s disease, supporting the idea that the accumulation of amyloid is the original event that precipitates the formation of tangles and severe neuronal death.

However, the causal role of amyloid has been hard to prove or disprove. So far, animal experiments have not helped, because putting human Alzheimer’s disease genes into rodents causes them to readily produce plaques, but does not result in tangles or cell death.

To create a better model of human disease, Se Hoon Choi and Young-Hye Kim in Tanzi/Kim labs started with human neural stem cells programmed to produce high levels of the toxic amyloid protein. When they grew the cells in standard conditions, flat on a dish in a pool of liquid, the cells formed neurons and made lots of amyloid, but no plaques or tangles.

Then Kim had a brainstorm. He realized the brain is not made of liquid, Tanzi explained. “The brain is made of gel. So he thought, let’s grow the cells in the same type of gelatinous substrate that the brain is made of.”

That was the key, Tanzi said.  “When Kim grew the cells in gel, he was able to get not only amyloid, but he got plaques. And then when he waited a little longer, he saw tangles, real tangles.”

This progression from plaques to tangles had never been seen before in animal models or human cells. “We start to see the plaques around 6 weeks, and get tangles around eight or nine weeks and then the cell death may come after that,” Tanzi said.

Importantly, the investigators could stop the appearance of plaques and tangles by treating the cells with chemicals that block the production of amyloid protein. “Our work says that in Alzheimer’s, it’s the plaques that get you to the tangles,” Tanzi said. Tangles could be prevented independently of amyloid, they showed, using a compound that blocked the excess phosphorylation of tau that precedes tangle formation.

Tanzi’s lab is a leader in the discovery of new treatments that interfere with amyloid production, and the new cell model will greatly accelerate that effort.

 “This new system – which can be adapted to other neurodegenerative disorders – should revolutionize drug discovery in terms of speed, costs and physiologic relevance to disease,” says Tanzi.  “Testing drugs in mouse models that typically have brain deposits of either plaques or tangles, but not both, takes more than a year and is very costly.  With our three-dimensional model that recapitulates both plaques and tangles, we now can screen hundreds of thousands of drugs in a matter of months without using animals in a system that is considerably more relevant to the events occurring in the brains of Alzheimer’s patients.”

Tanzi and Kim are now testing 1,200 drugs currently marketed for other purposes, plus several thousand investigational new drugs in their system, to see if any of them any of them inhibit the appearance of plaques and tangles, or just tangles. “The idea is that we could potentially repurpose some of those that show activity in our model,” Tanzi explained. That would save time in the drug development process.

One caveat of the model is that it does not account for the important role of inflammation in Alzheimer’s disease. “We know that plaques come very early, and they cause some inflammation, “ Tanzi said. But as the disease progresses, inflammation picks up and “really pushes the disease forward,” Tanzi said. “At the end, inflammation likely kills more neurons than the plaques and tangles that caused it.”

To account for that, Tanzi says they are currently developing a different 3D system using inflammatory brain microglia cells. Ultimately, they aim to combine the two so they have neurons, plaques, tangles and microglia all in one dish.

Tanzi is the Kennedy Professor of Child Neurology and Mental Retardation, and Kim is an assistant professor of Neurology at Harvard Medical School.  Se Hoon Choi, PhD, and Young Hye Kim of the MGH Genetics and Aging Research Unit are co-lead authors of the paper, which was published in Nature. The study was supported by a grant from the Cure Alzheimer’s Fund and by National Institute of Health grants.

To read the full paper published in Nature, please click here.