Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder, characterized by synaptic degeneration associated with fibrillar aggregates of the amyloid-ß peptide and the microtubule-associated protein tau. The progression of neurofibrillary degeneration throughout the brain during AD follows a predictive pattern which provides the basis for the neuropathological staging of the disease. This pattern of selective neuronal vulnerability against neurofibrillary degeneration matches the regional degree of neuronal plasticity and inversely recapitulates ontogenetic and phylogenetic brain development which links neurodegenerative cell death to neuroplasticity and brain development. Here, we summarize recent evidence for a loss of neuronal differentiation control as a critical pathogenetic event in AD, associated with a reactivation of the cell cycle and a partial or full replication of DNA giving rise to neurons with a content of DNA above the diploid level. Neurons with an aneuploid set of chromosomes are also present at a low frequency in the normal brain where they appear to be well tolerated. In AD, however, where the number of aneuploid neurons is highly increased, a rather selective cell death of neurons with this chromosomal aberrancy occurs. This finding add aneuploidy to the list of critical molecular events that are shared between neurodegeneration and oncogenesis. It defines a molecular signature for neuronal vulnerability and directs our attention to a failure of neuronal differentiation control as a critical pathogenetic event and potential therapeutic target in AD.
Similar content being viewed by others
References
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
Arendt T (2001) Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience 102:723–765
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913
Arendt T, Brückner MK, Gertz HJ, Marcova L (1998) Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain. Neuroscience 83(4):991–1002
Braak H, Braak E (1996) Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol 92(2):197–201
Arendt T, Holzer M, Stobe A, Gartner U, Luth HJ, Bruckner MK, Ueberham U (2000) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death. Ann N Y Acad Sci 920:249–255
Arendt T (1993) Neuronal dedifferentiation and degeneration in Alzheimer's disease. Biol Chem Hoppe-Seyler 374:911–912
Heintz N (1993) Cell-death and the cell-cycle—a relationship between transformation and neurodegeneration. Trends Biochem Sci 18:157–159
Arendt T, Holzer M, Gartner U (1998) Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease. J Neural Transm 105:949–960
Arendt T, Rodel L, Gartner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport 7:3047–3049
Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci 18:2801–2807
Ding XL, Husseman J, Tomashevski A, Nochlin D, Jin LW, Vincent I (2000) The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer's disease. Am J Pathol 157:1983–1990
McShea A, Harris PL, Webster KR, Wahl AF, Smith MA (1997) Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol 150:1933–1939
Nagy Z, Esiri MM, Cato AM, Smith AD (1997) Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol (Berl) 94:6–15
Nagy Z, Esiri MM, Smith AD (1997) Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol (Berl) 93:294–300
Smith TW, Lippa CF (1995) Ki-67 immunoreactivity in Alzheimer's disease and other neurodegenerative disorders. J Neuropathol Exp Neurol 54:297–303
Vincent I, Jicha G, Rosado M, Dickson DW (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci 17:3588–3598
Arendt T (2003) Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the Dr. Jekyll and Mr. Hyde concept of Alzheimer's disease or the yin and yang of neuroplasticity. Progr Neurobiol 71:83–248
Herrup K, Arendt T (2002) Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer's disease. J Alzheimers Dis 4:243–247
Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378
Arendt T, Brückner MK (2007) Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity. Biochim Biophys Acta 1772(4):413–421
Schmetsdorf S, Gartner U, Arendt T (2005) Expression of cell cycle-related proteins in developing and adult mouse hippocampus. Int J Dev Neurosci 23:101–112
Schmetsdorf S, Gärtner U, Arendt T (2007) Constitutive expression of functionally active cyclin-dependent kinases and their binding partners suggests noncanonical functions of cell cycle regulators in differentiated neurons. Cereb Cortex 17:1821–1829
Frank CL, Li-H T (2009) Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity. Neuron 62(3):312–326
Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. PNAS 82:4531–4534
Esiri MM, Chance SA (2006) Vulnerability to Alzheimer's pathology in neocortex: the roles of plasticity and columnar organization. J Alzheimers Dis 9(3 Suppl):79–89
Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, Litchfield S, Barnetson L (1996) Clustering of pathological features in Alzheimer's disease: clinical and neuroanatomical aspects. Dementia 7:121–127
Kosik KS, Rogers J, Kowall NW (1987) Senile plaques are located between apical dendritic clusters. J Neuropathol Exp Neurol 46:1–11
Buldyrev SV, Cruz L, Gomez-Isla T, Gomez-Tortosa E, Havlin S, Le R, Stanley HE, Urbanc B, Hyman BT (2000) Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias. PNAS 97:5039–5043
Duyckaerts C, Hauw JJ, Piette F, Rainsard C, Poulain V, Berthaux P, Escourolle R (1985) Cortical atrophy in senile dementia of the Alzheimer type is mainly due to a decrease in cortical length. Acta Neuropathol 66:72–74
Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10:184–192
Chance SA, Casanova MF, Switala AE, Crow TJ, Esiri MM (2006) Minicolumn thinning in temporal lobe association cortex but not primary auditory cortex in normal human ageing. Acta Neuropathol 111:459–464
Colombo JA, Quinn B, Puissant V (2002) Disruption of astroglial interlaminar processes in Alzheimer's disease. Brain Res Bull 58:235–242
Armstrong RA, Cairns NJ, Lantos PL (1997) Dementia with Lewy bodies: clustering of Lewy bodies in human patients. Neurosci Lett 224(1):41–44
Armstrong RA, Cairns NJ, Lantos PL (1998) Clustering of Pick bodies in patients with Pick’s disease. Neurosci Lett 242(2):81–84
Casanova MF (2003) Modular concepts of brain organization and the neuropathology of psychiatric conditions. Psychiatr Res 118:101–102
Rapoport SI (1988) Brain evolution and Alzheimer's disease. Rev Neurol (Paris) 144:79–90
Kaushal D, Contos JJ, Treuner K, Yang AH, Kingsbury MA, Rehen SK, McConnell MJ, Okabe M, Barlow C, Chun J (2003) Alteration of gene expression by chromosome loss in the postnatal mouse brain. J Neurosci 23:5599–5606
Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J (2001) Chromosomal variation in neurons of the developing and adult mammalian nervous system. PNAS 98:13361–13366
Yurov YB, Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Kutsev SI, Pellestor F, Beresheva AK, Demidova IA, Kravets VS, Monakhov VV, Soloviev IV (2007) Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS One 2:e558
Martin O, Rubenstein JL (2001) A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci 2(11):780–790
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8:427–437
Kornack DR, Rakic P (1995) Radial and horizontal deployment of clonally related cells in the primate neocortex: relationship to distinct mitotic lineages. Neuron 15:311–321
Luskin MB, Parnavelas JG, Barfield JA (1993) Neurons, astrocytes, and oligodendrocytes of the rat cerebral cortex originate from separate progenitor cells: an ultrastructural analysis of clonally related cells. J Neurosci 13:1730–1750
Sidman RL, Rakic P (1973) Neuronal migration, with special reference to developing human brain: a review. Brain Res 62:1–35
Rakic P (1988) Specification of cerebral cortical areas. Science 241:170–176
Mountcastle VB (1957) Modality and topographic properties of single neurons of cat’s somatic sensory cortex. J Neurophysiol 20:408–434
Mountcastle VB (1978) An organizing principle for cerebral function. In: Edelman GM, Mountcastle VB (eds) The mindful brain. MIT Press, Cambridge, pp 7–50
Mountcastle VB (1997) The columnar organization of the neocortex. Brain 120:701–722
Kriegstein A, Noctor S, Martinez-Cerdeno V (2006) Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neurosci 7:883–890
Krubitzer L, Kahn DM (2003) Nature versus nurture revisited: an old idea with a new twist. Prog Neurobiol 70:33–52
Kornack DR, Rakic P (1998) Changes in cell-cycle kinetics during the development and evolution of primate neocortex. PNAS 95:1242–1246
Takahashi T, Nowakowski RS, Caviness VS Jr (1995) The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J Neurosci 15:6046–6057
Hill RS, Walsh CA (2005) Molecular insights into human brain evolution. Nature 437:64–67
Cáceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C (2003) Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci U S A 100(22):13030–13035
Enard W, Khaitovich P, Klose J, Zöllner S, Heissig F, Giavalisco P, Nieselt-Struwe K, Muchmore E, Varki A, Ravid R, Doxiadis GM, Bontrop RE, Pääbo S (2002) Intra- and interspecific variation in primate gene expression patterns. Science 296(5566):340–343
Gu J, Gu X (2003) Induced gene expression in human brain after the split from chimpanzee. Trends Genet 19(2):63–65
Uddin M, Wildman DE, Liu G, Xu W, Johnson RM, Hof PR, Kapatos G, Grossman LI, Goodman M (2004) Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. PNAS 101(9):2957–2962
Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I, Dietzsch J, Steigele S, Do HH, Weiss G, Enard W, Heissig F, Arendt T, Nieselt-Struwe K, Eichler EE, Pääbo S (2004) Regional patterns of gene expression in human and chimpanzee brains. Genome Res 14(8):1462–1473
Khaitovich P, Weiss G, Lachmann M, Hellmann I, Enard W, Muetzel B, Wirkner U, Ansorge W, Pääbo S (2004) A neutral model of transcriptome evolution. PLoS Biol 2(5):E132
Thomson RY, Frazer SC (1954) The deoxyribonucleic acid content of individual rat cell nuclei. Exp Cell Res 6:367–383
Ueberham E, Lindner R, Kamprad M, Hiemann R, Hilger N, Woithe B, Mahn D, Cross M, Sack U, Gebhardt R, Arendt T, Ueberham U (2008) Oval cell proliferation in p16INK4a expressing mouse liver is triggered by chronic growth stimuli. J Cell Mol Med 12:622–638
Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Yurov YB (2009) Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain. Human Mol Gen 18:2656–2669
Iourov IY, Vorsanova SG, Liehr T, Yurov YB (2009) Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning. Neurobiol Dis 34:212–220
Kingsbury MA, Friedman B, McConnell MJ, Rehen SK, Yang AH, Kaushal D, Chun J (2005) Aneuploid neurons are functionally active and integrated into brain circuitry. PNAS 102:6143–6147
Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, Arendt T (2007) Aneuploidy and DNA replication in the normal human brain and Alzheimer's disease. J Neurosci 27:6859–6867
Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BSV, Kingsbury MA, Cabral KMS, McConnell MJ, Anliker B, Fontanoz M, Chun J (2005) Constitutional aneuploidy in the normal human brain. J Neurosci 25:2176–2180
Vorsanova SG, Yurov YB, Iourov IY (2010) Human interphase chromosomes: a review of available molecular cytogenetic technologies. Mol Cytogen 3:1
Westra JW, Peterson SE, Yung YC, Mutoh T, Barral S, Chun J (2008) Aneuploid mosaicism in the developing and adult cerebellar cortex. J Comp Neurol 507:1944–1951
Westra JW, Rivera RR, Bushman DM, Yung YC, Peterson SE, Barral S, Chun J (2010) Neuronal DNA content variation (DCV) with regional and individual differences in the human brain. J Comp Neurol 518:3981–4000
Brodsky VJ, Kusc AA (1962) Changes in the number of polyploid cells during postnatal development of rat tissue. Sci USSR 147:713–716
Müller H (1962) Cytophotometrische DNS-Messungen an Ganglienzellkernen des Nucleus dentatus beim Menschen. Naturwiss 49:243
Lapham LW (1965) The tetraploid DNA content of normal human Purkinje cells and its development during the perinatal period: a quantitative cytochemical study. Excerpta Med (Amst) Congr Ser 100:445–449
Lapham LW (1968) Tetraploid DNA content of Purkinje neurons of human cerebellar cortex. Science 159:310–312
Herman CJ, Lapham LW (1969) Neuronal polyploidy and nuclear volumes in the cat central nervous system. Brain Res 15:35–48
Mares V, Lodin Z, Sácha J (1973) A cytochemical and autoradiographic study of nuclear DNA in mouse Purkinje cells. Brain Res 53:273–289
Bernocchi G, Manfredi Romanini MG (1977) Chromatin cytochemistry as a tool for the functional interpretation of Purkinje’s cells in rat cerebellum. Riv Istochim Norm Patol 21:131–142
Bernocchi G, Redi CA, Scherini E (1979) Feulgen-DNA content of the Purkinje neuron: “diploid” or “tetraploid”? Basic Appl Histochem 23:65–70
Bernocchi G (1975) Contenuto in DNA e area nucleare dei neuroni durante l’istogenese cerebellare del ratto. Instituto Lombardo (Rend Sc) 109:143–161
Bregnard A, Knüsel A, Kuenzle CC (1975) Are all the neuronal nuclei polyploid? Histochemistry 43:59–61
Brodsky VJ, Sokolova GA, Manakova TE (1971) Multiple increase of DNA in the Purkinje cells of cerebellum in ontogenesis of rats. Ontogeny (USSR) 2:33–36
Brodsky VY, Agroskin LS, Lebedev EA, Marshak TL, Papayan GV, Segal OL, Sokolova GA, Yarygin KN (1974) Stability and variations of amount of DNA in a population of cerebellum cells. Z Obshchei Biol 35:917–925
Lentz RD, Lapham LW (1969) A quantitative cytochemical study of the DNA content of neurons of rat cerebellar cortex. J Neurochem 16:379–384
Lentz RD, Lapham LW (1970) Postnatal development of tetraploid DNA content in rat Purkinje cells: a quantitative cytochemical study. J Neuropathol Exp Neurol 29:43–56
Marshak TL, Maresh V, Brodskii V (1978) Number of Purkinje cells with an increased DNA content in rat cerebellum. Kolichestvo kletok Purkin’e s uvelichennym soderzhaniem DNK v mozzhechke krysy. Tsitolog 20:651–656
Marshak TL, Petruchuk EM, Aref’eva AM, Shalunova NV, Brodskiĭ VI (1976) O soderzhanii DNK V kletkakh Purkin’e mozzhechka krys, spontanno infitsirovannykh virusom Kilkhema. Biulleten’ eksperimental’noĭ biologii i meditsiny 82:1274–1276
Sandritter W, Novokova V, Pilny J, Kiefer G (1967) Cytophotometrische Messungen des Nukleins ure- und Proteingehaltes von Ganglienzellen der Ratte während der postnatalen Entwicklung und im Alter. Zeitschr Zellforsch 80:145–152
Magkian I, Karalova EM (1975) [Basic factors in the polyploidization of cerebellar Purkinfe cells in chick embryogenesis. III. Kinetics of RNA and DNA in Purkinje cell nuclei]. Osenovnye faktory poliploidizatsii kletok Purkin’e mozzhechka v embriogeneze kur. III. Kinetika RNK i DNK v iadrakh kletok Purkin’e. Tsitolog 17:653–659
Herman CJ, Lapham LW (1968) DNA content of neurons in the cat hippocampus. Science 160:537
Bregnard A, Kuenzle CC, Ruch F (1977) Cytophotometric and autoradiographic evidence for post-natal DNA synthesis in neurons of the rat cerebral cortex. Exp Cell Res 107:151–157
Nováková V, Sandritter W, Schlueter G (1970) DNA content of neurons in rat central nervous system. Exp Cell Res 60:454–456
Svanidze IK (1967) Cytophotometry of DNA amounts in nuclei of neurons and gliacytes of the cerebral cortex of rats at different ontogenetic stages. J Gen Biol (USSR) 28:697–708
Museridze DP, Svanidze IK (1972) Quantitative analysis of DNA in the neurons of the visual cortex of the brain at the early stages of postnatal ontogenesis of guinea pigs. Sov J Dev Biol 3:430–434
Kut AA, Iarygin VN (1965) Polipliodiia odnoiadernykh i dvuiadernykh neĭronov v verkhnem sheĭnom uzle krolika. Tsitolog 7:228–233
Swartz FJ, Bhatnagar KP (1981) Are CNS neurons polyploid? A critical analysis based upon cytophotometric study of the DNA content of cerebellar and olfactory bulbar neurons of the bat. Brain Res 208:267–281
Bregnard A, Ruch F, Lutz H, Kuenzle CC (1979) Histones and DNA increase synchronously in neurons during early postnatal development of the rat forebrain cortex. Histochemistry 61:271–279
Kuenzle CC, Bregnard A, Hübscher U, Ruch F (1978) Extra DNA in forebrain cortical neurons. Exp Cell Res 113:151–160
Cohen J, Mares V, Lodin Z (1973) DNA content of purified preparations of mouse Purkinje neurons isolated by a velocity sedimentation technique. J Neurochem 20:651–657
Fujita S (1974) DNA constancy in neurons of the human cerebellum and spinal cord as revealed by Feulgen cytophotometry and cytofluorometry. J Comp Neurol 155:195–202
Fukuda M, Bohm N, Fujita S (1978) Cytophotometry and its biological application. Progr Histochem Cytochem 11:1–119
Mann DM, Yates PO, Barton CM (1978) The DNA content of Purkinje cells in mammals. J Comp Neurol 180:345–347
Mann DM, Yates PO (1973) Polyploidy in the human nervous system: Part 1. The DNA content of neurones and glia of the cerebellum. J Neurol Sci 18:183–196
Morselt AF, Braakman DJ, James J (1972) Feulgen-DNA and fast-green histone estimations in individual cell nuclei of the cerebellum of young and old rats. Acta Histochem 43:281–286
Duijndam WA, Smeulders AW, van Duijn P, Verweij AC (1980) Optical errors in scanning stage absorbance cytophotometry. I. Procedures for correcting apparent integrated absorbance values for distributional, glare, and diffraction errors. J Histochem Cytochem 28:388–394
Duijndam WA, van Duijn P, Riddersma SH (1980) Optical errors in scanning stage absorbance cytophotometry. II. Application of correction factors for residual distributional error, glare and diffraction error in practical cytophotometry. J Histochem Cytochem 28:395–400
Fujita S, Fukuda M, Kitamura T, Satoru Y (1972) Two-wave-length-scanning method in Feulgen cytophotometry. Acta Histochem Cytochem 5:146–152
Brodsky VJ, Marshak TL, Mares V, Lodin Z, Fülöp Z, Lebedev EA (1979) Constancy and variability in the content of DNA in cerebellar Purkinje cell nuclei. A cytophotometric study. Histochemistry 59:233–248
Mares V, van der Ploeg M (1980) Cytophotometric re-investigation of DNA content in Purkinje cells of the rat cerebellum. Histochemistry 69:161–167
Marshak TL, Mares V, Brodsky VY (1985) An attempt to influence DNA content in postmitotic Purkinje cells of the cerebellum. Acta Histochem 76:193–200
Morillo SM, Escoll P, de La Hera A, Frade JM (2010) Somatic tetraploidy in specific chick retinal ganglion cells induced by nerve growth factor. PNAS 107:109–114
McConnell MJ, Kaushal D, Yang AH, Kingsbury MA, Rehen SK, Treuner K, Helton R, Annas EG, Chun J, Barlow C (2004) Failed clearance of aneuploid embryonic neural progenitor cells leads to excess aneuploidy in the Atm-deficient but not the Trp53-deficient adult cerebral cortex. J Neurosci 24:8090–8096
Yurov YB, Iourov IY, Monakhov VV, Soloviev IV, Vostrikov VM, Vorsanova SG (2005) The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. J Histochem Cytochem 53:385–390
Blaschke AJ, Staley K, Chun J (1996) Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex. Development 122:1165–1174
Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 21:2661–2668
Yurov YB, Vostrikov VM, Vorsanova SG, Monakhov VV, Iourov IY (2001) Multicolor fluorescent in situ hybridization on post-mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. Brain Dev 23(Suppl 1):186–190
Gimelbrant A, Hutchinson JN, Thompson BR, Chess A (2007) Widespread monoallelic expression on human autosomes. Science 318:1136–1140
Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, Wang J, Pan Y, Gabuzda DH, Li C, Prolla TA, Yankner BA (2008) Evolution of the aging brain transcriptome and synaptic regulation. PLoS One 3(10):e3329
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Månér S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841
Hassold T, Hunt P (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2:280–291
Rezaie R, Daly EM, Cutter WJ, Murphy DG, Robertson DM, Delisi LE, Mackay CE, Barrick TR, Crow TJ, Roberts N (2009) The influence of sex chromosome aneuploidy on brain asymmetry. Am J Med Genet B Neuropsychiatr Genet 150B(1):74–85
Bigner SH, Mark J, Bigner DD (1990) Cytogenetics of human brain tumors. Cancer Genet Cytogenet 47:141–154
Yamada K, Kasama M, Kondo T, Shinoura N, Yoshioka M (1994) Chromosome studies in 70 brain tumors with special attention to sex chromosome loss and single autosomal trisomy. Cancer Genet Cytogenet 73:46–52
Guttenbach M, Koschorz B, Bernthaler U, Grimm T, Schmid M (1995) Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet 57:1143–1150
Jacobs PA, Court Brown WM, Doll R (1961) Distribution of human chromosome counts in relation to age. Nature 191:1178–1180
Nowinski GP, Van Dyke DL, Tilley BC, Jacobsen G, Babu VR, Worsham MJ, Wilson GN, Weiss L (1990) The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am J Hum Genet 46:1101–1111
Ly DH, Lockhart DJ, Lerner RA, Schultz PG (2000) Mitotic misregulation and human aging. Science 287:2486–2492
Buckton KE, Whalley LJ, Lee M, Christie JE (1983) Chromosome changes in Alzheimer's presenile dementia. J Med Genet 20:46–51
King RC, Stansfiled WD (1990) A dictionary of genetics, 4th edn. Oxford University Press, New York
Moorhead PS, Heyman A (1983) Chromosome studies of patients with Alzheimer's disease. Am J Med Genet 14:545–556
Nordenson I, Adolfsson R, Beckman G, Bucht G, Winblad B (1980) Chromosomal abnormality in dementia of Alzheimer type. Lancet 1(8166):481–482
Thomas P, Fenech M (2008) Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease. Mutagenesis 23:57–65
Gorman P, Roylance R (2006) Fluorescence in situ hybridization and comparative genomic hybridization. Meth Mol Med 120:269–295
Nordensson I, Beckman G, Adolfsson R, Bucht G, Winblad B (1983) Cytogenetic changes in patients with senile dementia. Age Ageing 12(4):285–295
Smith A, Broe GA, Williamson M (1983) Chromosome aneuploidy in Alzheimer's disease. Clin Genet 24:54–57
Ward BE, Cook RH, Robinson A, Austin JH (1979) Increased aneuploidy in Alzheimer disease. Am J Med Genet 3:137–144
White BJ, Crandall C, Goudsmit J, Morrow CH, Alling DW, Gajdusek DC, Tijio JH (1981) Cytogenetic studies of familial and sporadic Alzheimer disease. Am J Med Genet 10:77–89
Jacobs PA, Baikie AG, Court Brown WM, Strong JA (1959) The somatic chromosomes in mongolism. Lancet 1(7075):710
Lejeune J, Turpin R, Gautier M (1959) Mongolism: a chromosomal disease (trisomy). Bull Acad Natl Med 143:256–265
Lichter P, Cremer T, Tang CJ, Watkins PC, Manuelidis L, Ward DC (1988) Rapid detection of human chromosome 21 aberrations by in situ hybridization. PNAS 85:9664–9668
Zheng YL, Ferguson-Smith MA, Warner JP, Ferguson-Smith ME, Sargent CA, Carter NP (1992) Analysis of chromosome 21 copy number in uncultured amniocytes by fluorescence in situ hybridization using a cosmid contig. Prenat Diagn 12:931–943
DeLisi LE, Friedrich U, Wahlstrom J, Boccio-Smith A, Forsman A, Eklund K, Crow TJ (1994) Schizophrenia and sex chromosome anomalies. Schizophr Bull 20:495–505
Kaplan AR (1970) Chromosomal mosaicisms and occasional acentric chromosomal fragments in schizophrenic patients. Biol Psychiatry 2:89–94
Kumra S, Wiggs E, Krasnewich D, Meck J, Smith AC, Bedwell J, Fernandez T, Jacobsen LK, Lenane M, Rapoport JL (1998) Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders. J Am Acad Child Adolesc Psych 37:292–296
Kunugi H, Lee KB, Nanko S (1999) Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophr Res 40:43–47
Mors O, Mortensen PB, Ewald H (2001) No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes. Psychol Med 31:425–430
Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Meerabux J, Hattori E, Ichimiya T, Yoshikawa T (2001) Karyotype analysis of 161 unrelated schizophrenics: no increased rates of X chromosome mosaicism or inv(9), using ethnically matched and age-stratified controls. Schizophr Res 52:171–179
Callier P, Faivre L, Cusin V, Marle N, Thauvin-Robinet C, Sandre D, Rousseau T, Sagot P, Lacombe E, Faber V, Mugneret F (2005) Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome. Am J Med Genet A 137:204–207
Jacquemont S, Bocéno M, Rival JM, Méchinaud F, David A (2002) High risk of malignancy in mosaic variegated aneuploidy syndrome. Am J Med Genet 109(1):17–21
Kajii T, Ikeuchi T, Yang ZQ, Nakamura Y, Tsuji Y, Yokomori K, Kawamura M, Fukuda S, Horita S, Asamoto A (2001) Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants. Am J Med Genet 104:57–64
Kawame H, Sugio Y, Fuyama Y, Hayashi Y, Suzuki H, Kurosawa K, Maekawa K (1999) Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature. J Hum Genet 44:219–224
Limwongse C, Schwartz S, Bocian M, Robin NH (1999) Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma. Am J Med Genet 82:20–24
Thiel G, Losanowa T, Kintzel D, Nisch G, Martin H, Vorpahl K, Witkowski R (1992) Karyotypes in 90 human gliomas. Cancer Genet Cytogenet 58:109–120
Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Arendt T, Mosch B, Morawski M (2009) Neuronal aneuploidy in health and disease: a cytomic approach to understand the molecular individuality of neurons. Int J Mol Sci 10:1609–1627
Lenz D, Mosch B, Bocsi J, Arendt T, Tarnok A (2004) Assessment of DNA replication in central nervous system by laser scanning cytometry. In: Nicolau DV (ed) Imaging, manipulation, and analysis of biomolecules, cells, and tissues II. 27–28 January 2004, San Jose, California, USA. SPIE, Bellingham, pp 146–156
Mosch B, Mittag A, Lenz D, Arendt T, Tárnok A (2006) Laser scanning cytometry in human brain slices. Cytometry A 69(3):135–138
Arendt T, Brückner MK, Mosch B, Lösche A (2010) Selective cell death of hyperploid neurons in Alzheimer's disease. Am J Pathol 177:15–20
Geller LA, Potter H (1999) Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease. Neurbiol Dis 6:167–179
Iourov IY, Vorsanova SG, Yurov YB (2006) Chromosomal variation in mammalian neuronal cells: known facts and attractive hypotheses. Int Rev Cytol 249:143–191
Iourov IY, Vorsanova SG, Yurov YB (2008) Chromosomal mosaicism goes global. Mol Cytogen 1:26
Potter H (1991) Review and hypothesis: Alzheimer disease and Down syndrome-chromosome 21 nondisjunction may underlie both disorders. Am J Med Genet 48:1192–1200
Boeras DI, Granic A, Padmanabhan J, Crespo NC, Rojiani AM, Potter H (2008) Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging 29:319–328
Granic A, Padmanabhan J, Norden M, Potter H (2010) Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP. Mol Biol Cell 21:511–520
Iourov I, Vorsanova S, Yurov Y (2011) Genomic landscape of the Alzheimer's disease brain: chromosome instability—aneuploidy, but not tetraploidy—mediates neurodegeneration. Neurodegen Dis 8:35–37, discussion 38–40
Kuenzle CC (1985) Enzymology of DNA replication and repair in the brain. Brain Res 357:231–245
Lovell MA, Xie C, Markesbery WR (2000) Decreased base excision repair and increased helicase activity in Alzheimer's disease brain. Brain Res 855:116–123
Mazzarello P, Poloni M, Spadari S, Focher F (1992) DNA repair mechanisms in neurological diseases: facts and hypotheses. J Neurol Sci 112:4–14
Nouspikel T, Hanawalt PC (2003) When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer's disease. Bioessays 25:168–173
Yang AH, Kaushal D, Rehen SK, Kriedt K, Kingsbury MA, McConnell MJ, Chun J (2003) Chromosome segregation defects contribute to aneuploidy in normal neural progenitor cells. J Neurosci 23:10454–10462
Potter H (2005) Cell cycle and chromosome segregation defects in Alzheimer's disease. In: Copani A, Nicoletti F (eds) Cell-cycle mechanisms and neuronal death. Landes, Georgetown, pp 55–78
Potter H (1991) Review and hypothesis: Alzheimer disease and Down syndrome–chromosome 21 nondisjunction may underlie both disorders. Am J Human Gen 48:1192–1200
Cherry LM, Funk J, Lesser JM, Lesam M (1992) Gender differences and their interpretation of genetic instability in Alzheimer's disease. Mutat Res 275:57–76
Migliore L, Boni G, Bernardini R, Trippi F, Colognato R, Fontana I, Coppedè F, Sbrana I (2006) Susceptibility to chromosome malsegregation in lymphocytes of women who had a Down syndrome child in young age. Neurobiol Aging 27:710–716
Migliore L, Botto N, Scarpato R, Petrozzi L, Cipriani G, Bonuccelli U (1999) Preferential occurence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients. Cytogenet Cell Genet 87:41–46
Migliore L, Testa A, Scarpato R, Pavese N, Petrozzi L, Bonuccelli U (1997) Spontaneous and induced aneuploidy in peripheral blood lymphocytes of patients with Alzheimer's disease. Human Genet 101:299–305
Percy ME, Markovic VD, Dalton AJ, McLachlan DRC, Berg JM, Rusk ACM, Somerville MJ, Chodakowski B, Andrews DF (1993) Age-associated chromosome 21 loss in Down syndrome: possible relevance to mosaicism and Alzheimer's disease. Am J Med Genet 45:584–588
Schupf N, Kapell D, Lee JH, Ottman R, Mayeux R (1994) Increased risk of Alzheimer's disease in mothers of adults with Down's syndrome. Lancet 344:353–356
Li J, Xu M, Zhou H, Ma J, Potter H (1997) Alzheimer presenilins in the nuclear membrane, interphase kinetochores and centrosomes suggest a role in chromosome segregation. Cell 90:917–927
Arendt T (2008) Differentiation and de-differentiation—neuronal cell cycle regulation during development and age-related neurodegenerative disorders. In: Lajtha A, Perez-Polo JR, Rossner S (eds) Handbook of neurochemistry and molecular neurobiology. Development and aging changes in the nervous system, 3rd edn. Springer, New York, pp 157–213
Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer's disease? J Cell Biol 132:413–425
Arendt T (2000) Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain. Neurobiol Aging 21(6):783–796
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Arendt, T. Cell Cycle Activation and Aneuploid Neurons in Alzheimer's Disease. Mol Neurobiol 46, 125–135 (2012). https://doi.org/10.1007/s12035-012-8262-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-012-8262-0