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

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  1. This paper stands apart from amongst the swath of papers that describe changes in AD brain as a means of delineating the progressive neurodegenerative mechanism operating in the disease. It is a beautiful example of how a fairly simple and straightforward technical approach can translate into priceless information if combined with careful inquisition, evaluation, and insight. The study explores cases of mild cognitive impairment (MCI) as a precursor to AD. Previous evidence suggests that not all cases of MCI may develop AD, but may evolve into other neurological conditions. The presence of cell cycle markers in every one of the 10 MCI cases studied signifies a role for a cell cycle-driven process, not only in AD, but in other age-associated dementias, as well.

    Taken together with the positive results in many different neuronal populations, this study arrives at the conclusion that ectopic reentrance into the cell cycle is a "unified" mechanism of neurodegeneration, indicative of a "single disease process" in all neurons in many disease states. The presence of cell cycle markers in neurons may, therefore, constitute one of the most reliable harbingers of death. The estimation of the duration of this death mechanism in neurons, based on the number of neurons affected, is intriguing in light of practical approaches for intervening with disease. Undoubtedly, the findings presented here need to be substantiated by examining many more cases, but even if wrong, this is an elegant contribution to the scientific literature.

  2. Traditionally, neurons have been considered to be "locked" into the G0 phase of the cell cycle. The release of a differentiated cell from the resting G0 phase results in its entry into the first gap (G1) phase, during which the cell prepares for DNA replication in the S phase. This is followed by the second gap phase (G2) and mitosis (M phase). In mammalian neurons, the reexpression of cell cycle markers has been linked with the occurrence of certain types of neuronal cell death. The interpretation of these findings (Lee et al., 1992) has been that a neuron is committed to the permanent cessation of cell division, so if for any reason it is forced to reenter the cell cycle after this commitment, it dies.

    Such failure of regulation of the cell cycle has been observed in Alzheimer’s disease brain. Notably, ectopic expression of cdc2, cdk4, p16, Ki-67, cyclin B1, and cyclin D have been reported in pathologically affected or vulnerable neurons in AD brain (Liu et al., 1995; Smith and Lippa, 1995; Vincent et al., 1996; 1997; Arendt et al., 1996; McShea et al., 1997; Busser et al., 1998). The latter found abnormal appearance of cell cycle markers in regions of AD brain where cell death is extensive, and Chow et al. (1998) found increases in expression of genes encoding cell cycle proteins in single neurons in late-stage relative to early-stage AD brain. A number of the cell cycle regulators have been detected in vulnerable neurons prior to lesion formation (Busser et al., 1998; Kondratick and Vandre, 1996; Vincent et al., 1998). Patrick et al. (1999) have shown that p25, a truncated form of p35, the regulatory subunit of Cdk5, is increased in AD brain.

    What are the consequences of the aberrant expression of cell cycle proteins for the neuropathology of AD? For some time, some have argued that this abnormal expression of cell cycle proteins in neurons in AD brain was merely an epiphenomenon of the disease, and that it did not necessarily indicate that neurons were actually entering the cell cycle. However, Yang and colleagues (2001) made the remarkable demonstration that a significant number of vulnerable hippocampal pyramidal (four percent vs. zero percent in control hippocampus) and basal forebrain neurons in AD brain have fully or partially replicated their DNA, showing that they have completed the S phase. These results provide indisputable evidence that neurons in affected regions of AD brain have indeed transitioned from G0 to S phase.

    Yang and colleagues now follow up on this earlier work by showing, in a beautifully written paper, that markers of the G0-to-G1 phase, of the S phase, and of the G2 phase of the cell cycle are seen in neurons in the brains of individuals clinically categorized with mild cognitive impairment (MCI). Many (although not all) individuals with MCI go on to develop AD within a few years. Therefore, MCI can be viewed in many respects as a very early stage of AD.

    There are three notable points made in this paper.

    1. Cell cycle immunopositive neurons in the hippocampus, nucleus basalis, and entorhinal cortex of MCI cases were present at frequencies equivalent to, or greater than (in the case of the entorhinal cortex), their frequencies in AD cases. Therefore, abnormal cell cycle events can be considered one of the earliest pathological markers in AD, suggesting strongly that they represent a proximal cause of the neurodegeneration in this disease.

    2. The frequency of cell cycle immunopositive neurons in the AD-vulnerable brain regions (five-10 percent) is relatively high, in both MCI and AD cases. As the authors point out, if cell death due to aberrant activation of the cell cycle were rapid, then at any given snapshot in time, less than 0.01 percent of cells would show cell cycle events. The much higher percentage than that of cells that are cell cycle positive suggests "that the cells are ‘stuck’ for many months (possibly up to one year) in a cycle they cannot complete." This has therapeutic implications, of course. If, at any given moment in time, a large number of neurons in early- and late-stage AD have already embarked on their one-year journey towards death, then neurons will continue to die even if a palliative therapy is being applied. It will appear that the therapy is failing to work if the duration of the clinical trial is too short.

    3. All the MCI cases studied showed aberrant cell cycle events in neurons, despite the fact that not all individuals with MCI proceed to AD. Some develop other neurological disorders. These data suggest that cell cycle abnormalities may be at the root of other neurodegenerative diseases in addition to AD, and are consistent with such studies as the recent paper by Nguyen et al. (2003) showing that cell cycle abnormalities may be at the heart of amyotrophic lateral sclerosis (ALS).

    References:

    . Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport. 1996 Nov 25;7(18):3047-9. PubMed.

    . Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci. 1998 Apr 15;18(8):2801-7. PubMed.

    . Expression profiles of multiple genes in single neurons of Alzheimer's disease. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9620-5. PubMed.

    . Alzheimer's disease neurofibrillary tangles contain mitosis-specific phosphoepitopes. J Neurochem. 1996 Dec;67(6):2405-16. PubMed.

    . Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992 Sep 24;359(6393):288-94. PubMed.

    . Detection of a Cdc2-related kinase associated with Alzheimer paired helical filaments. Am J Pathol. 1995 Jan;146(1):228-38. PubMed.

    . Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol. 1997 Jun;150(6):1933-9. PubMed.

    . Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci. 2003 Mar 15;23(6):2131-40. PubMed.

    . Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999 Dec 9;402(6762):615-22. PubMed.

    . Ki-67 immunoreactivity in Alzheimer's disease and other neurodegenerative disorders. J Neuropathol Exp Neurol. 1995 May;54(3):297-303. PubMed.

    . Mitotic mechanisms in Alzheimer's disease?. J Cell Biol. 1996 Feb;132(3):413-25. PubMed.

    . Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci. 1997 May 15;17(10):3588-98. PubMed.

    . Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease. Neurobiol Aging. 1998 Jul-Aug;19(4):287-96. PubMed.

    . DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001 Apr 15;21(8):2661-8. PubMed.

References

News Citations

  1. Oxidative Stress Triggers Neuronal Cell-Cycle Reentry
  2. COX-2 in Neurodegeneration: Does It Wake Up a Sleeping Cell Cycle?

Other Citations

  1. live discussion

Further Reading

No Available Further Reading

Primary Papers

  1. . Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci. 2003 Apr 1;23(7):2557-63. PubMed.