Pictures in molecular medicine: contemplating Alzheimer's disease as cancer: a loss of cell-cycle control.

Contemplating Alzheimer's disease as cancer: a loss of cell-cycle controlThe nerve cells of the adult brain are born predominantly during embryogenesis, and as development proceeds, the addition of new nerve cells slows to a barely detectable trickle. By the time a human being nears the end of life most of their nerve cells have been in a post-mitotic state for seven to nine decades. The means by which cells accomplish this feat of suspended animation are unknown, but there are no apparent failures of the cell cycle arrest mechanism.During the past few years several laboratories have suggested that if a nerve cell violates the prohibition against cell division it will die rather than divide. The principle was first suggested when a powerful oncogene was expressed specifically in maturing Purkinje cells in transgenic mice. Unexpectedly, transgenic Purkinje cells began replicating their DNA but subsequently died 1xIn vivo viability of postmitotic Purkinje neurons requires pRb family member function. Feddersen, R.M. et al. Mol. Cell. Neurosci. 1995; 6: 153–167Crossref | PubMed | Scopus (58)See all References1. Next, researchers found that the activation of cell cycle processes is part of the mechanism by which developmental failure of trophic support leads to nerve cell death 2xThe induction of multiple cell cycle events precedes target-related neuronal death. Herrup, K. and Busser, J.C. Development. 1995; 121: 2385–2395PubMedSee all References, 3xAnalysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Freeman, R. et al. Neuron. 1994; 12: 343–355Abstract | Full Text PDF | PubMed | Scopus (499)See all References.Now, several laboratories have explored the role of cell cycle processes in late-onset neurodegenerative disease. Our laboratory was one of several that provided immunocytochemical evidence for the presence of cell cycle activators (Fig. 1Fig. 1) as well as inhibitors in neurons of Alzheimer's disease brain. But the cell cycle is a highly regulated phenomenon.Fig. 1Immunocytochemical evidence for the re-expression of proliferating cell nuclear antigen (PCNA), a subunit of DNA polymerase. (a) Although normally found only in dividing cells, hippocampal neurons in Alzheimer's disease brain show occasional cells with significant expression of this protein. (b) Cells from a similar region of an age-matched, non-demented control show no evidence of expression.View Large Image | Download PowerPoint SlideOur laboratory adapted cytogenetics techniques such as fluorescent in situ hybridization (FISH) to analyze the DNA directly. We discovered that the chromosome complement in 4% of the hippocampal pyramidal cells in Alzheimer's disease has doubled 4xMice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Yang, Y. et al. J. Neurosci. 2001; 21: 2661–2668PubMedSee all References4. Using either short centromeric FISH probes or long probes to unique sequences we were able to show that these neurons had up to four copies of each locus instead of the expected two – direct evidence that a coordinated DNA duplication had occurred (Fig. 2Fig. 2). No evidence of mitosis was found, suggesting the cells arrested at or near the G2 phase of the cell cycle.Fig. 2Fluorescence in situ hybridization for unique sites in the human genome. Neurons of the adult brain should all be diploid and display no more than two sites of hybridization. (a) In the Alzheimer's disease hippocampal neuron illustrated, four spots are found (white arrows) indicating that cells have arrested in G-phase, and that coordinated DNA duplication has occurred. (b) Cells from control subjects always have two spots or fewer.View Large Image | Download PowerPoint SlideThe implication of these findings is that the neurons in the Alzheimer's disease brain are subjected to a mitotic pressure that drives them to attempt a cell cycle they cannot complete. In most cancers, a gene mutation disrupts cell cycle suppression leading to the clonal expansion of a single dysregulated cell. If our model is correct, then the problem in Alzheimer's disease is nearly the exact opposite: although the nerve cells themselves remain genetically intact, extrinsic factors that promote cell division increase until, one by one, the most susceptible neurons divide and die.