Insight Into Alzheimer's Disease.
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Tesseur and Wyss-Coray hypothesized that by protecting neurons, TGF-beta may help prevent Alzheimer's disease. If the TGF-beta pathway is turned off, the brain becomes more susceptible to a toxic buildup of proteins. "We tried to see what happens if we block neurons from getting this beneficial signal," said Wyss-Coray.
To investigate that hypothesis, the researchers genetically engineered mice with a defect similar to the one they found in the brains of Alzheimer's patients: These mice had brain cells that could no longer respond to TGF-beta's salutary signal. The mutation did not directly affect the TGF-beta protein, which is found throughout the body. Instead, it blocked brain cells' ability to detect and respond to the molecule. This way, the TGF-beta pathway was active everywhere else besides the neurons of the mice. Unable to receive the beneficial TGF-beta signal, the rodents with the broken pathway showed signs of Alzheimer's disease. Brain cells died as the mice grew older, and the cells failed to make connections to other brain cells, a defining trait of the cells.
The results were even more striking when the researchers blocked the TGF-beta pathway in mice that were already susceptible to an Alzheimer's-like disease. These mice had a rare version of a human gene that causes people to develop Alzheimer's in their 40s and 50s, said Wyss-Coray. Blocking TGF-beta in these mice caused the animals to display signs of Alzheimer's disease that researchers had until then failed to recreate. The brains of the mice had more dead cells and a protein buildup characteristic of the disease in humans.
"Our study offers the possibility that if you have a reduction in this pathway, then you can accelerate the pathology," said Wyss-Coray. The flip side is that activating the TGF-beta pathway may offer a treatment for Alzheimer's, he said. In the past, researchers have tried using molecules that work like TGF-beta to provide protection against Alzheimer's, but they had trouble getting them into the brain, said Wyss-Coray. Those proteins, or the cells used to carry them, are too large to enter the brain through the bloodstream.
To sidestep that problem, Wyss-Coray is working with chemists to identify small molecules - drugs - that can boost the TGF-beta pathway in neurons. Because of TGF-beta's many roles in the body, Wyss-Coray will also be searching for molecules that act only on brain cells. He will test whether these drugs can ameliorate the Alzheimer's-like disease he created in mice. Wyss-Coray said that for now the strategy is "wishful thinking," but based on the results of this study, it's worth trying.
Alzheimer's Donation
Donate Online Now
.
Tesseur and Wyss-Coray hypothesized that by protecting neurons, TGF-beta may help prevent Alzheimer's disease. If the TGF-beta pathway is turned off, the brain becomes more susceptible to a toxic buildup of proteins. "We tried to see what happens if we block neurons from getting this beneficial signal," said Wyss-Coray.
To investigate that hypothesis, the researchers genetically engineered mice with a defect similar to the one they found in the brains of Alzheimer's patients: These mice had brain cells that could no longer respond to TGF-beta's salutary signal. The mutation did not directly affect the TGF-beta protein, which is found throughout the body. Instead, it blocked brain cells' ability to detect and respond to the molecule. This way, the TGF-beta pathway was active everywhere else besides the neurons of the mice. Unable to receive the beneficial TGF-beta signal, the rodents with the broken pathway showed signs of Alzheimer's disease. Brain cells died as the mice grew older, and the cells failed to make connections to other brain cells, a defining trait of the cells.
The results were even more striking when the researchers blocked the TGF-beta pathway in mice that were already susceptible to an Alzheimer's-like disease. These mice had a rare version of a human gene that causes people to develop Alzheimer's in their 40s and 50s, said Wyss-Coray. Blocking TGF-beta in these mice caused the animals to display signs of Alzheimer's disease that researchers had until then failed to recreate. The brains of the mice had more dead cells and a protein buildup characteristic of the disease in humans.
"Our study offers the possibility that if you have a reduction in this pathway, then you can accelerate the pathology," said Wyss-Coray. The flip side is that activating the TGF-beta pathway may offer a treatment for Alzheimer's, he said. In the past, researchers have tried using molecules that work like TGF-beta to provide protection against Alzheimer's, but they had trouble getting them into the brain, said Wyss-Coray. Those proteins, or the cells used to carry them, are too large to enter the brain through the bloodstream.
To sidestep that problem, Wyss-Coray is working with chemists to identify small molecules - drugs - that can boost the TGF-beta pathway in neurons. Because of TGF-beta's many roles in the body, Wyss-Coray will also be searching for molecules that act only on brain cells. He will test whether these drugs can ameliorate the Alzheimer's-like disease he created in mice. Wyss-Coray said that for now the strategy is "wishful thinking," but based on the results of this study, it's worth trying.
posted by Valery Yermalitsky at
7:24 AM
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