Disease Scientists Discover a Pathway in the Cause of Alzheimer's
September 26, 2007
The plaques and tangles may be the sign posts for Alzheimer’s disease, but Peter Davies, PhD, says believes that he has discovered the road itself– and it is a pathway that he and his colleagues in the field have missed after decades spent exploring the terrain of the diseased brain.
Dr. Davies, scientific director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at The Feinstein Institute for Medical Research, says that the switch that drives cell cycle of neurons, which is a one-time event when the neuron is born, is somehow tripped and reactivated late in life. It is this catastrophic occurrence that sets the stage for cell death.
“Neurons don’t divide but for some reason the machinery for cell division is turned on in the brains of Alzheimer’s patients,” explained the scientist. “These are differentiated neurons that are not built to divide. The machinery is making enzymes and proteins that the cells are not supposed to see, and this just isn’t good for the cell.”
Dr. Davies will discuss these novel findings on Tuesday, September 25, at a research symposium sponsored by the Alzheimer’s Association of New York City. He spent most of his scientific career studying the tau tangles – one of the two hallmark signs of the diseased Alzheimer’s brain. It was during one of these experiments that one of his colleagues, Inez Vincent, PhD, noticed that one of the antibodies made to label the tau pathology in the brain also picked out dividing cells. (Today, many scientists use this antibody as a marker for cancer cells, which lack the normal brakes on cell division.) Dr. Davies said that the finding was so “heretical” that it took two years to get the paper published. The publication of the study in the Journal of Cell Biology in 1996 sent a handful of scientists back to their labs to see whether they could replicate it. And they did.
At the time, Dr. Davies’ lab was at the Albert Einstein College of Medicine in the Bronx, and they designed an experiment to turn on the cell cycle in brains of adult mice. They put a viral oncogene into differentiated neurons and watched as pathological events unfolded. “This was a lethal event for the mice,” said Dr. Davies. But what he wasn’t expecting was this: The mice developed the same brain pathology – an accumulation of tau protein – that is seen in Alzheimer’s. And subsequent studies show that there may even be amyloid deposits, the other hallmark of a diseased brain. In fact, most scientists believe that amyloid is the main event in the disease, and therapeutic targets are aimed at stopping amyloid from accumulating in the brain.)
But if Davies is right, it’s the unbridled and unexpected cell division that is the initial event. “There was an abundance of tau pathology,” Dr. Davies said. “There were big holes in the brain where there should have been neurons, and suggestions of amyloid deposits.”
He said that turning on the cell cycle in the neurons – a feat that was done using a tetracycline-regulating system that carried a promoter that targets only neurons – was sufficient to trigger cell death and produce some of the pathology seen in Alzheimer’s.
At around the same time last year, Pasko Rakic, MD, of Yale University, reported that abnormal activation of the cell cycle was linked to the death of cells following a stroke. “Our idea gained credibility overnight,” said Dr. Davies. The question remained: What was turning on the cell cycle in the Alzheimer’s brain?
For the answer, Dr. Davies and his colleagues turned to the cancer literature. “In cancer, there is a whole series of oncogenes that are turned on,” he explained. This triggers cell division. But in the Alzheimer’s brains he studied, the machinery for cell division was turned on and it spewed forth the same ingredients that dividing cells need to grow, but the cells themselves showed no signs of actually dividing.
Now the critical issue is to identify the factors that turn on this machinery “It all comes back to identifying what turns on this pathway,” the scientist said. “Alzheimer’s doesn’t start with tau or amyloid. They are the sign posts that tell us that the cell cycle has been turned on.” Again, that would mean that a drug that stops this machinery could prevent both of these pathological events. More importantly, it would stop the brain cells from dying, Davies added.
They have now identified the abnormal cell cycle circuitry in the brains of Alzheimer’s patients as well as those in the earliest stages of memory impairment who died from other causes. “We still have to prove a causal relationship,” Dr. Davies said.
About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org or www.molmed.org.
Media Contact: Jamie Talan 516-562-1232/631-682-8781
Dr. Davies, scientific director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at The Feinstein Institute for Medical Research, says that the switch that drives cell cycle of neurons, which is a one-time event when the neuron is born, is somehow tripped and reactivated late in life. It is this catastrophic occurrence that sets the stage for cell death.
“Neurons don’t divide but for some reason the machinery for cell division is turned on in the brains of Alzheimer’s patients,” explained the scientist. “These are differentiated neurons that are not built to divide. The machinery is making enzymes and proteins that the cells are not supposed to see, and this just isn’t good for the cell.”
Dr. Davies will discuss these novel findings on Tuesday, September 25, at a research symposium sponsored by the Alzheimer’s Association of New York City. He spent most of his scientific career studying the tau tangles – one of the two hallmark signs of the diseased Alzheimer’s brain. It was during one of these experiments that one of his colleagues, Inez Vincent, PhD, noticed that one of the antibodies made to label the tau pathology in the brain also picked out dividing cells. (Today, many scientists use this antibody as a marker for cancer cells, which lack the normal brakes on cell division.) Dr. Davies said that the finding was so “heretical” that it took two years to get the paper published. The publication of the study in the Journal of Cell Biology in 1996 sent a handful of scientists back to their labs to see whether they could replicate it. And they did.
At the time, Dr. Davies’ lab was at the Albert Einstein College of Medicine in the Bronx, and they designed an experiment to turn on the cell cycle in brains of adult mice. They put a viral oncogene into differentiated neurons and watched as pathological events unfolded. “This was a lethal event for the mice,” said Dr. Davies. But what he wasn’t expecting was this: The mice developed the same brain pathology – an accumulation of tau protein – that is seen in Alzheimer’s. And subsequent studies show that there may even be amyloid deposits, the other hallmark of a diseased brain. In fact, most scientists believe that amyloid is the main event in the disease, and therapeutic targets are aimed at stopping amyloid from accumulating in the brain.)
But if Davies is right, it’s the unbridled and unexpected cell division that is the initial event. “There was an abundance of tau pathology,” Dr. Davies said. “There were big holes in the brain where there should have been neurons, and suggestions of amyloid deposits.”
He said that turning on the cell cycle in the neurons – a feat that was done using a tetracycline-regulating system that carried a promoter that targets only neurons – was sufficient to trigger cell death and produce some of the pathology seen in Alzheimer’s.
At around the same time last year, Pasko Rakic, MD, of Yale University, reported that abnormal activation of the cell cycle was linked to the death of cells following a stroke. “Our idea gained credibility overnight,” said Dr. Davies. The question remained: What was turning on the cell cycle in the Alzheimer’s brain?
For the answer, Dr. Davies and his colleagues turned to the cancer literature. “In cancer, there is a whole series of oncogenes that are turned on,” he explained. This triggers cell division. But in the Alzheimer’s brains he studied, the machinery for cell division was turned on and it spewed forth the same ingredients that dividing cells need to grow, but the cells themselves showed no signs of actually dividing.
Now the critical issue is to identify the factors that turn on this machinery “It all comes back to identifying what turns on this pathway,” the scientist said. “Alzheimer’s doesn’t start with tau or amyloid. They are the sign posts that tell us that the cell cycle has been turned on.” Again, that would mean that a drug that stops this machinery could prevent both of these pathological events. More importantly, it would stop the brain cells from dying, Davies added.
They have now identified the abnormal cell cycle circuitry in the brains of Alzheimer’s patients as well as those in the earliest stages of memory impairment who died from other causes. “We still have to prove a causal relationship,” Dr. Davies said.
About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org or www.molmed.org.
Media Contact: Jamie Talan 516-562-1232/631-682-8781