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Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, Arendt T. Aneuploidy and DNA replication in the normal human brain and Alzheimer's disease. J Neurosci. 2007 Jun 27;27(26):6859-67. PubMed.
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University of Wisconsin
Cycling to Nowhere
The paper by Arendt and colleagues presents compelling evidence for DNA synthesis in terminally differentiated neurons of the AD brain, and raises a number of other questions. It is intriguing to speculate whether the increase in cyclin B1 observed in half of the aged control subjects is indicative of an increased attempt by these aging neurons to re-enter the cell cycle. Is this a precursor stage to MCI? Would these individuals have developed AD if they had lived longer? Does cyclin B1 expression remain elevated after the cells reach tetraploidy?
Given that these polyploidy neurons are unlikely to survive (Yang et al., 2003), it seems likely that the quantitation of polyploidy and cell cycle related markers at the terminal stage of the disease is a gross underestimation of the mitogenic stimulus reaching neurons in the aging brain.
Recently we identified an upregulation in the expression of osteopontin, a protein that is intimately involved in cell cycle progression and cell adhesion (Wung et al., 2007) in the AD brain that may be a response to neuronal remodeling induced by neuron re-entry into the cell cycle.
It remains to be determined what signals are driving differentiated postmitotic neurons back into the cell cycle. The paper by Arendt and colleagues provides strong evidence for the “Cell Cycle Hypothesis of AD.” In this respect we have postulated that the major changes in HPG axis hormones with aging (decreased sex steroids, decreased inhibin resulting in increased activin signaling, increased GnRH, increased gonadotropins; Bowen and Atwood, 2004) alter the growth-differentiation dynamic of cells throughout the body. Put another way, the changes in reproductive hormones that occur with aging are somewhat similar to those seen during fetal life and this growth-oriented profile may induce cell proliferation. In those tissues that attempt division but are unable to undergo cytokinesis (neurons, cardiomyocytes, fibroblasts), cell loss leads to loss of function and disease, while those tissues containing cells that can divide (i.e., reproductive tissues, colonic cells, lung, liver, pancreas, etc.) continue to accumulate mutations and tend to develop neoplasia.
Bowen RL, Atwood CS. Living and dying for sex. A theory of aging based on the modulation of cell cycle signaling by reproductive hormones. Gerontology. 2004 Sep-Oct;50(5):265-90. PubMed.
Wung JK, Perry G, Kowalski A, Harris PL, Bishop GM, Trivedi MA, Johnson SC, Smith MA, Denhardt DT, Atwood CS. Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the Alzheimer's disease brain. Curr Alzheimer Res. 2007 Feb;4(1):67-72. PubMed.
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 Apr 1;23(7):2557-63. PubMed.View all comments by Craig Atwood
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