Researchers have uncovered a key piece of missing evidence in the proof that nerve cell death in Alzheimer's disease is caused by a failed attempt at cell division. They have found a significant number of brain cells in Alzheimer's patients with extra copies of chromosomes, showing attempts at cell division in cells that are not supposed to divide. This effort to divide is the likely cause of the nerve degeneration and dementia in Alzheimer's disease, say the researchers.
"It's almost as if Alzheimer's disease were a novel form of cancer," says Karl Herrup, senior author of the findings published in a paper by researchers from Case Western Reserve University's School of Medicine and University Hospitals of Cleveland in the April 15 issue of the "Journal of Neuroscience." Cancer is characterized by uncontrolled cell division. In this study, scientists found uncontrolled cell division, arrested in the midst of the process, is the likely cause of the nerve cell destruction.
"We've been able to show that the duplication of the DNA has occurred in neurons in the Alzheimer's disease brain. By looking at four locations in the genome, we can be pretty confident that the DNA duplicated completely, not just in a few spots," says Herrup, a professor of neurosciences. According to Herrup, memory loss in Alzheimer's disease is always associated with the accumulation of strange deposits in the brain known as plaques and tangles. Most investigators agree that these deposits are central to the disease, but are not in and of themselves the cause of memory loss. The clinical symptoms are more closely tied to the nerve cell death, but the links between plaques and death were unclear. "The simplest view is that plaques are directly toxic to neurons. The cell division hypothesis puts a different spin on this idea," he says.
While previous studies from this team and others have provided indirect evidence of cell division in Alzheimer's disease through the detection of proteins usually involved in cell division, this paper supplies direct evidence of cell division. The scientists found a significant number of cells in brain tissue from Alzheimer's patients which had four copies of chromosomes in them, whereas normal cells have two, and only two, copies.
Cells normally make extra copies of chromosomes when they divide, but the extra copies are passed on equally to their offspring cells. The brain cells of Alzheimer's patients apparently enter the cell division process, make the extra chromosomes, but never create new cells to pass on the extra copies.
Says Herrup, "We know now almost precisely where the cell is stopped in the division process and we know something even more important: Because it's stopped there and not able to proceed, its nucleus is basically out of balance with its surrounding cell structures. Normally, the cell machinery expects two copies of a given gene, but in Alzheimer's disease there are four because the DNA is replicated. Since the cell hasn't divided it is sitting with twice as much DNA as it should have. We speculate that is the root cause of the nerve cell death."
The researchers do not know what triggers the cells to begin a cycle for which they are not programmed, but a theory they put forth with other CWRU/UHC colleagues hypothesizes that the plaques which are a hallmark of Alzheimer's disease brain cells trigger an inflammatory response in the brain, and that this response brings with it proteins that trigger cell division.
Herrup said the findings of the paper open new doors to develop therapeutics that could prevent signals for the inflammatory response from reaching the cells or to prevent the cells from responding to the signals to divide.
The other authors are Yan Yang and David Geldmacher, both also with CWRU and UHC. Herrup is the director of the University Alzheimer Center at CWRU and UHC.