- Alzheimer’s disease
- Cell cycle
- Fluorescence in situ hybridization
- Fluorescence-activated cell sorting
- Cerebral cortex
Alzheimer’s disease (AD) is characterized by extensive neuronal death in distinct brain regions, including the frontal cortex and hippocampus, although the specific mechanisms of neuronal degeneration in AD remain a topic of intense scientific pursuit. One model for cell death in AD postulates that abortive cell cycle events in neurons, including tetraploidy, precede neuronal death, and novel therapeutics based on suppressing cell cycle re-entry are being pursued. Using DNA content fluorescence-activated cell sorting combined with fluorescence in situ hybridization and immunostaining, we analyzed neuronal nuclei from postmortem human brain samples from the frontal cortex and hippocampus of nondiseased and AD patients for evidence of tetraploidy. Here, we show that tetraploid nuclei are similarly prevalent in AD and control brains and are exclusively non-neuronal, contrasting with an absence of tetraploid neurons. Our findings demonstrate that neuronal tetraploidy is nonexistent in the AD brain and intimate a reevaluation of neuronal cell cycle re-entry as a therapeutic target for AD.
Copyright © 2009 S. Karger AG, Basel
- Price DL, Tanzi RE, Borchelt DR, Sisodia SS: Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 1998;32:461–493.
- Morrison JH, Hof PR: Life and death of neurons in the aging brain. Science 1997;278:412–419.
- Tanzi RE, Bertram L: Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005;120:545–555.
- Mancuso M, Siciliano G, Filosto M, Murri L: Mitochondrial dysfunction and Alzheimer’s disease: new developments. J Alzheimers Dis 2006;9:111–117.
- Shcherbatykh I, Carpenter DO: The role of metals in the etiology of Alzheimer’s disease. J Alzheimers Dis 2007;11:191–205.
- Herrup K, Yang Y: Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 2007;8:368–378.
- Nagy Z, Esiri MM, Smith AD: Expression of cell division markers in the hippocampus in Alzheimer’s disease and other neurodegenerative conditions. Acta Neuropathol 1997;93:294–300.
- Busser J, Geldmacher DS, Herrup K: Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci 1998;18:2801–2807.
- Smith MZ, Nagy Z, Esiri MM: Cell cycle-related protein expression in vascular dementia and Alzheimer’s disease. Neurosci Lett 1999;271:45–48.
- Nagy Z, Esiri MM, Cato AM, Smith AD: Cell cycle markers in the hippocampus in Alzheimer’s disease. Acta Neuropathol 1997;94:6–15.
- 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;23:2557–2563.
- Hoozemans JJ, Bruckner MK, Rozemuller AJ, Veerhuis R, Eikelenboom P, Arendt T: Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J Neuropathol Exp Neurol 2002;61:678–688.
- Vincent I, Jicha G, Rosado M, Dickson DW: Aberrant expression of mitotic Cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 1997;17:3588–3598.
- McShea A, Harris PL, Webster KR, Wahl AF, Smith MA: Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol 1997;150:1933–1939.
- Yang Y, Geldmacher DS, Herrup K: DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 2001;21:2661–2668.
- Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BS, Kingsbury MA, Cabral KM, McConnell MJ, Anliker B, Fontanoz M, Chun J: Constitutional aneuploidy in the normal human brain. J Neurosci 2005;25:2176–2180.
- Yurov YB, Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Kutsev SI, Pellestor F, Beresheva AK, Demidova IA, Kravets VS, Monakhov VV, Soloviev IV: Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE 2007;2:e558.
- Riga D, Riga S: Lipofuscin and ceroid pigments in aging and brain pathology. A review. I. Biochemical and morphological properties. Rom J Neurol Psychiatry 1995;33:121–136.
- Braak E: On the fine structure of the external glial layer in the isocortex of man. Cell Tissue Res 1975;157:367–390.
- Marusich MF, Furneaux HM, Henion PD, Weston JA: Hu neuronal proteins are expressed in proliferating neurogenic cells. J Neurobiol 1994;25:143–155.
- Mullen RJ, Buck CR, Smith AM: Neun, a neuronal specific nuclear protein in vertebrates. Development 1992;116:201–211.
- Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O: Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A 1997;94:10432–10437.
- Rass U, Ahel I, West SC: Defective DNA repair and neurodegenerative disease. Cell 2007;130:991–1004.
- Park DS, Morris EJ, Bremner R, Keramaris E, Padmanabhan J, Rosenbaum M, Shelanski ML, Geller HM, Greene LA: Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J Neurosci 2000;20:3104–3114.
- Mazumder S, Plesca D, Almasan A: A Jekyll and Hyde role of cyclin E in the genotoxic stress response: switching from cell cycle control to apoptosis regulation. Cell Cycle 2007;6:1437–1442.
- Muller-Tidow C, Ji P, Diederichs S, Potratz J, Baumer N, Kohler G, Cauvet T, Choudary C, van der Meer T, Chan WY, Nieduszynski C, Colledge WH, Carrington M, Koeffler HP, Restle A, Wiesmuller L, Sobczak-Thepot J, Berdel WE, Serve H: The cyclin A1-CDK2 complex regulates DNA double-strand break repair. Mol Cell Biol 2004;24:8917–8928.
- Lovell MA, Markesbery WR: Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 2007;35:7497–7504.
- Subba Rao K: Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol 2007;3:162–172.
- Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA: Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883–891.
- West MJ, Coleman PD, Flood DG, Troncoso JC: Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994;344:769–772.
- Bhardwaj RD, Curtis MA, Spalding KL, Buchholz BA, Fink D, Bjork-Eriksson T, Nordborg C, Gage FH, Druid H, Eriksson PS, Frisen J: Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci U S A 2006;103:12564–12568.
- Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisen J: Retrospective birth dating of cells in humans. Cell 2005;122:133–143.
- Bloom J, Cross FR: Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol 2007;8:149–160.
- Bauer S, Patterson PH: The cell cycle-apoptosis connection revisited in the adult brain. J Cell Biol 2005;171:641–650.
- Boekhoorn K, Joels M, Lucassen PJ: Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis 2006;24:1–14.
- Lu KP, Zhou XZ: The prolyl isomerase pin1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 2007;8:904–916.
- Arendt T, Holzer M, Stobe A, Gartner U, Luth HJ, Bruckner MK, Ueberham U: Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer’s disease that eventually results in cell death. Ann N Y Acad Sci 2000;920:249–255.
Dr. Jerold Chun
The Scripps Research Institute, ICND 118
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Received: September 8, 2008
Accepted after revision: March 16, 2009
Published online: September 9, 2009
Number of Print Pages : 9
Number of Figures : 5, Number of Tables : 0, Number of References : 37
Vol. 6, No. 5-6, Year 2009 (Cover Date: February 2010)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)
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