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The Journal of Neuroscience, June 27, 2007, 27(26):6859-6867; doi:10.1523/JNEUROSCI.0379-07.2007

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Neurobiology of Disease
Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

Birgit Mosch,^1,4 Markus Morawski,^1,3 Anja Mittag,² Dominik Lenz,² Attila Tarnok,² and Thomas Arendt¹

¹Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, ²Department of Pediatric Cardiology, Cardiac Center Leipzig, and ³Interdisciplinary Center of Clinical Research, Faculty of Medicine, University of Leipzig, D-04109 Leipzig, Germany, and ⁴Institute of Radiopharmacy, Department of Radiopharmaceutical Biology, Research Center Dresden-Rossendorf, D-01328 Dresden, Germany

Correspondence should be addressed to Dr. Thomas Arendt, Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, Jahnallee 59, D-04109 Leipzig, Germany. Email: aret{at}medizin.uni-leipzig.de

Reactivation of the cell cycle, including DNA replication, might play a major role in Alzheimer's disease (AD). A more than diploid DNA content in differentiated neurons might alternatively result from chromosome mis-segregation during mitosis in neuronal progenitor cells. It was our objective to distinguish between these two mechanisms for aneuploidy and to provide evidence for a functional cell cycle in AD. Using slide-based cytometry, chromogenic in situ hybridization, and PCR amplification of alu-repeats, we quantified the DNA amount of identified cortical neurons in normal human brain and AD and analyzed the link between a tetraploid DNA content and expression of the early mitotic marker cyclin B1. In the normal brain, the number of neurons with a more than diploid content amounts to 10%. Less than 1% of neurons contains a tetraploid DNA content. These neurons do not express cyclin B1, most likely representing constitutional tetraploidy. This population of cyclin B1-negative tetraploid neurons, at a reduced number, is also present in AD. In addition, a population of cyclin B1-positive tetraploid neurons of 2% of all neurons was observed in AD. Our results indicate that at least two different mechanisms need to be distinguished giving rise to a tetraploid DNA content in the adult brain. Constitutional aneuploidy in differentiated neurons might be more frequent than previously thought. It is, however, not elevated in AD. In addition, in AD some neurons have re-entered the cell cycle and entirely passed through a functional interphase with a complete DNA replication.

Key words: cell cycle; cyclin B1; neurodegeneration; chromogenic in situ hybridization; CISH; slide-based cytometry; SBC; quantitative real-time PCR

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Received Jan. 28, 2007; revised April 20, 2007; accepted May 15, 2007.

Correspondence should be addressed to Dr. Thomas Arendt, Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, Jahnallee 59, D-04109 Leipzig, Germany. Email: aret{at}medizin.uni-leipzig.de

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