. Involvement of DNA damage and repair systems in neurodegenerative process. Toxicol Lett. 2003 Apr 4;139(2-3):99-105. PubMed.

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  1. Oncogenic Processes in Alzheimer’s Disease: A Common Link?
    While the Alzheimer’s disease (AD) research community has historically focused almost exclusively on how the two hallmark lesions of the disease, namely senile plaques and neurofibrillary tangles, are involved in the pathogenesis of AD, in recent years investigators have ventured outside these constraints and proposed alternate hypotheses. In such instances, hypotheses such as oxidative stress and cell cycle dysregulation, while first viewed skeptically, have proven to represent extremely early events in the disease that precede the appearance of senile plaques and neurofibrillary tangles (Vincent et al., 1998; Nunomura et al., 2001). The paper published by Uberti et al., 2003 in many ways follows in this vein by proposing, as we have previously seen (Raina et al., 1999; Raina et al., 2000; Zhu et al., 2000), that neurodegenerative disease in many ways proximally resembles what we see early on in oncogenic processes. They demonstrate that a number of neuronal cell lines, as well as primary neurons, respond to a variety of insults, including the Aβ25-35 neurotoxic peptide and oxidative insult with H2O2, by upregulating p53, which plays a crucial role in cell cycle checkpoint and DNA damage and repair processes. They then go on to demonstrate that the two members of the mismatch repair complex, MSH2 and PCNA, are likewise upregulated in response to such insults in neuronal cell lines.

    The data put forth in this paper is compelling but, in many ways, should not come as a great surprise. First, and perhaps most importantly, the dysregulation of cell cycle processes has been established as an important pathogenic mechanism in AD (McShea et al., 1997; Vincent et al., 1998; reviewed in Raina et al., 2000; Alzheimer Research Forum, 2002). Cell cycle dysregulation over a protracted time course can be viewed as fulfilling the necessary elements that form the criteria for oncogenesis (Raina et al., 1999, 2000). As such, the fact that the cell cycle checkpoint marker p53 should be imbalanced is somewhat expected. It is also intuitive that DNA would be among the other macromolecules that are targets of oxidative stress, catalogued in AD. In fact, nucleic acids have been shown to be extensively oxidatively modified in the disease, as demonstrated by the accumulation of 8-hydroxyguanosine moieties (Nunomura et al., 1999). As such, one would expect that the neurons would mount a defense to such damage by upregulation of DNA repair mechanisms, including p53 and the mismatch repair. The effect that cell cycle dysregulation would have on normally quiescent, postmitotic cells in unclear. In other dividing cells populations, it has been well-documented that the combination of cell cycle dysfunction and altered DNA repair mechanisms, combined with the overriding of apoptosis, can select for transformed cells, thus leading to cancer. However, it seems likely that neurons, which are a highly differentiated cell population with extensive intercellular connections, would be incapable of the full "dedifferentiation" that would be required for them to complete a successful cell division. While the consequences of the dysregulated cell cycle in these cells still has to be fully elucidated, it is very possible that the phenotype seen in the vulnerable neuronal populations in AD may, in fact, represent the end result of this process. Indeed, this dysmitotic phenotype in AD can be viewed as an oncogenic phenotype, the persistence of which leads to global dysfunction in these vulnerable neuronal populations and ultimately to debility and death.

    See also:

    Vincent I, Nagy Z, Neve R, Herrup K, Milton N, Smith M, Wolozin B, Chen Y, Lu KP, Kinoshita J, Strobel G, Hallows J, Bowser R, Feinstein D, Atwood CS, Maiese K (2002) Transcript of Live Discussion: The cell cycle in Alzheimer’s disease: let’s unite around division! Alzheimer’s Research Forum, 2002.

    References:

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

    . Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.

    . Neuronal RNA oxidation in Alzheimer's disease and Down's syndrome. Ann N Y Acad Sci. 1999;893:362-4. PubMed.

    . The role of cell cycle-mediated events in Alzheimer's disease. Int J Exp Pathol. 1999 Apr;80(2):71-6. PubMed.

    . Cyclin' toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res. 2000 Jul 15;61(2):128-33. PubMed.

    . Involvement of DNA damage and repair systems in neurodegenerative process. Toxicol Lett. 2003 Apr 4;139(2-3):99-105. PubMed.

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

    . Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci. 2000 Jul-Aug;18(4-5):433-7. PubMed.

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