STANFORD, Calif. - A peacekeeper in the body's defenses against infection may hold the key to understanding - and eventually treating - Alzheimer's disease. Researchers at the Stanford University School of Medicine discovered that when a molecule responsible for dialing down the immune system malfunctions in the brain cells of mice, the rodents develop symptoms of the degenerative brain disease.
The finding, published in the November issue of the Journal of Clinical Investigation, offers researchers an insight into how humans may develop Alzheimer's, said the study's senior author Tony Wyss-Coray, PhD, associate professor of neurology and a researcher at the Veterans Affairs Palo Alto Health Care System.
Alzheimer's disease is characterized by an excessive buildup of proteins into plaques and tangles of cellular gunk that are likely to cause brain cells to die and lose their connections to other neurons. But for the most part, scientists do not understand the underlying biological problems behind Alzheimer's, making it difficult for doctors to treat, let alone cure.
"We don't have a treatment that alters the course of the disease," said Wyss-Coray.
Wyss-Coray and Ina Tesseur, PhD, an instructor in the Department of Neurology, examined thin slices of the brains of Alzheimer's patients who had died, and discovered abnormally low levels of a molecule involved in controlling the body's response to infection. That molecule allows the brain to detect and respond to TGF-beta, or transforming growth factor, a protein teeming through our bodies, involved in fighting infection, stopping cancer and perhaps keeping brain cells alive.
No other researchers had seen this change before, so Tesseur and Wyss-Coray set out to investigate whether it had some connection to Alzheimer's disease. They 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.
Co-authors of the study included Kun Zou, PhD; Elisabeth Berber, PhD; Judith Van Can, and Amy Lin, PhD, who all were involved in the research while at the medical school's Department of Neurology. The John Douglas French Alzheimer's Foundation, the Alzheimer's Association and the National Institutes of Health funded the research.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
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