. 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.

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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.

    View all comments by Inez Vincent
  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).

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    View all comments by Rachael Neve