16 April 2003. What happens when the protein machinery that drives the cell division cycle gets activated in non-dividing cells such as neurons? The cells will most likely die. Recent evidence suggests that just this type of scenario plays out in the brains of Alzheimer's patients (see ARF related news story, ARF related story, and live discussion). But at what stage of the disease does cell cycle reentry manifest itself? Pretty early, according to a report in this month's Journal of Neuroscience. The paper proposes that cell cycle reentry is a central mechanistic feature of AD throughout the disease process, not just a rare aberration in the latest stages.
Yan Yang and Karl Herrup at Case Western Reserve University, Cleveland, Ohio, and Eliot Mufson at Rush Presbyterian Medical Center, Chicago, examined brain samples of people who had died while suffering from mild cognitive impairment (MCI), a condition that in many cases will lead to full-blown Alzheimer's disease. Yang and colleagues used antibodies to test the presence of various cell cycle proteins in MCI, AD, and control brain samples taken at autopsy. Their data show that while few neurons tested positive in the control group, substantial numbers were present in the MCI and AD tissues, and that staining of MCI and AD tissues was almost indistinguishable. In the hippocampus, one of the first areas affected by the disease, both AD and MCI samples had robust staining for cyclin D1, DNA polymerase, and cyclin B1, proteins that are synthesized only during the G1, S and G2 phases of the cell cycle, respectively. The authors found a similar pattern in cells outside the hippocampus, such as in the entorhinal cortex and the nucleus basalis of Meynert, areas where AD-related cell cycle reentry has previously been documented.
For a quantitative comparison, the authors counted cell cycle-positive neurons in the hippocampal samples. Though they caution that the precise anatomical location of the samples varied from case to case, which could introduce some margin of error, the number of DNA polymerase- and cyclin D1-positive neurons were identical in both MCI and AD tissues, at five percent.
The latter value has significant implications. If AD neurons in-vivo died as soon as 12 hours after entry into the cell cycle (as shown in vitro and in developing mouse brain in vivo), and five percent of cells were dying at any one time (as shown in this study), then it would take less than a year for complete neuronal ablation. Obviously, this is not the case, leading Yang and colleagues to posit that these neurons are probably stuck for months or even a year in a cell cycle they cannot complete, and that they may not die by a typical apoptotic process. However fast these neurons die, the paper states that neurons die at the same rate in all stages of the disease process, and that neurons die from the same root cause (i.e., cell cycle reentry) throughout the disease.-Tom Fagan.
Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J. Neurosci. 2003 April 1;23:2557-2563. (Abstract)