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Cited by 56Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer's disease

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Nagy, Zsuzsanna·2005·Journal of Cellular and Molecular Medicine
DOI 10.1111/j.1582-4934.2005.tb00485.xPMC PMC6741636
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Abstract

Alzheimer's disease is the third biggest killer in the developed world after cancer and heart disease. Although the first description dates back to almost a century ago, we still do not understand the cellular-molecular mechanisms that lead to the development of the brain pathology. There is no efficient treatment for the patients. And even the symptomatic relief comes too late, because there is no diagnostic method that could identify patients before severe clinical symptoms develop. Almost every aspect of Alzheimer's research, whether on pathogenesis, diagnosis, risk factors or treatment strategies, seem to spark controversy nowadays. Studies that apparently contradict one another or propose alternate explanations are published monthly. Patients' hopes are raised with the announcement of each new drug trial. Then hope is lost when the trials fail. Ironically, while progressive research is hampered by apparent contradictions and lack of funding, the old dogmas survive in the textbooks and no real progress is made in terms of therapy. The purpose of this review is to take stock of the most discussed and most strongly opposing views on the pathogenesis of Alzheimer's disease. These views shape the Alzheimer field currently and some will hopefully one day shape the diagnostic and therapeutic approaches to the disease.

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  • Aberrant cell cycle re-entry of terminally differentiated post-mitotic neurons may play a critical role in the pathogenesis of Alzheimer's disease, supported by re-expression of several cell-cycle regulating proteins in vulnerable neurons.

    “Cumulative evidence suggests that aberrant cell cycle re-entry of the terminally differentiated post-mitotic neurons may play a critical role in the pathogenesis of AD, a theory that is supported by the re-expression of several cell-cycle regulating proteins in vulnerable neurons [187,188,189,190].”

    From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [189]

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Research works printed but not linked: 69

  1. Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA. Copernicus revisited: amyloid β in Alzheimer's disease. Neurobiol Aging. 2001; 22: 131-46.
  2. Begley S. Is Alzheimer's field blocking R&D into other causes? Wall Street Journal 2004.
  3. Begley S. Scientists fight a narrow view of Alzheimer's cause. Wall Street Journal 2004.
  4. Heston LL, Mastri AR. The genetics of Alzheimer's dis- ease: associations with hematologic malignancy and Down's syndrome. Arch Gen Psychiatry 1977; 34: 976-81.
  5. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L. Segregation of a missense mutation in the amy- loid precursor protein gene with familial Alzheimer's dis- ease. Nature 1991; 349: 704-6.
  6. Hardy J, Mullan M, Chartier-Harlan M, Brown J, Goate A, Rossor M. Molecular classification of Alzheimer's disease. The Lancet 1991; 337: 1342-3.
  7. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage. Dutch type. Science 1990; 248: 1124-6.
  8. Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis MG, Antonarakis SE, Martin JJ. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nat Genet. 1992; 1: 218-21.
  9. Clark RF, Goate AM. Molecular genetics of Alzheimer's disease. Arch Neurol. 1993; 50: 1164-72.
  10. Brunkan AL, Goate AM. Presenilin function and gamma-secretase activity. J Neurochem. 2005; 93: 769-92.
  11. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733-6.
  12. Kirazov E, Kirazov L, Bigl V, Schliebs R. Ontogenetic changes in protein level of amyloid precursor protein (APP) in growth cones and synaptosomes from rat brain and prenatal expression pattern of APP mRNA isoforms in developing rat embryo. Int J Dev Neurosci. 2001; 19: 287-96.
  13. Panegyres PK. The functions of the amyloid precursor protein gene. Rev Neurosci. 2001; 12: 1-39.
  14. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990; 248: 1122-4.
  15. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to poten- tially amyloidogenic derivatives. Science 1992; 255: 728-30.
  16. Selkoe DJ. Amyloid β-protein precursor: new clues to the genesis of Alzheimer's disease. Curr Opin Neurobiol. 1994; 4: 708-16.
  17. Kaneko I, Yamada N, Sakuraba Y, Kamenosono M, Tutumi S. Suppression of mitochondrial succinate dehy- drogenase, a primary target of β-amyloid, and its deriva- tive racemized at Ser residue. J Neurochem. 1995; 65: 2585-93.
  18. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homo- cysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998; 55: 1449-55.
  19. Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's dis- ease. Neurology 1988; 38: 1682-7.
  20. Nagy Z, Jobst KA, Esiri MM, Morris JH, King EM, MacDonald B, Litchfield S, Barnetson L, Smith AD. Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: clinico- pathologic correlations using three sets of pathologic diag- nostic criteria. Dementia 1996; 7: 76-81.
  21. Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, Litchfield S, Smith A, Barnetson L, Smith AD. Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria. Dementia 1995; 6: 21-31.
  22. Neve RL, Robakis NK. Alzheimer's disease: a re-exami- nation of the amyloid hypothesis. Trends Neurosci. 1998; 21: 15-9.
  23. Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ. Amyloid-β oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans. 2002; 30: 552-7.
  24. Kokubo H, Kayed R, Glabe CG, Yamaguchi H. Soluble Aβ oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer's disease brain. Brain Res. 2005; 1031: 222-8.
  25. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999; 155: 853-62.
  26. Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, Litchfield S, Smith A, Barnetson L, Smith AD. Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria. Dementia 1995; 6: 21-31.
  27. Wilcock GK, Esiri MM. Plaques, tangles and dementia. A quantitative study. J Neurol Sci. 1982; 56: 343-56.
  28. Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 1993; 16: 460-5.
  29. Drewes G, Lichtenberg-Kraag B, Doring F, Mandelkow EM, Biernat J, Goris J, Doree M, Mandelkow E. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 1992; 11: 2131-8.
  30. Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, Mandelkow E. Glycogen syn- thase kinase-3 and the Alzheimer-like state of micro- tubule-associated protein tau. FEBS Lett. 1992; 314: 315-21.
  31. Baumann K, Mandelkow EM, Biernat J, Piwnica- Worms H, Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinas- es cdk2 and cdk5. FEBS Lett. 1993; 336: 417-24.
  32. Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O'Connor M, Trojanowski JQ, Lee VM. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron 1994; 13: 989-1002.
  33. Iqbal K, Alonso AC, Gong CX, Khatoon S, Singh TJ, Grundke-Iqbal I. Mechanism of neurofibrillary degener- ation in Alzheimer's disease. Mol Neurobiol. 1994; 9: 119-23.
  34. Trojanowski J, Schmidt M, Shin R-W, Bramblett G, Rao D, Lee V-Y. PHFt(A68): from pathological marker to potential mediator of neuronal dysfunction and neuronal degeneration in Alheimer's disease. Clin Neurosci. 1993; 1: 184-91.
  35. Lee VM, Trojanowski JQ. The disordered neuronal cytoskeleton in Alzheimer's disease. Curr Opin Neurobiol. 1992; 2: 653-6.
  36. Arendt T, Rodel L, Gartner U, Holzer M. Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport 1996; 7: 3047-9.
  37. Nagy Z, Esiri MM, Smith AD. The cell division cycle and the pathophysiology of Alzheimer's disease. Neuroscience 1998; 87: 731-9.
  38. Vincent I, Zheng JH, Dickson DW, Kress Y, Davies P. Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease. Neurobiol Aging 1998; 19: 287-96.
  39. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001; 21: 2661-8.
  40. Arendt T. Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain. Neurobiol Aging. 2000; 21: 783-96.
  41. Nagy Z, Esiri MM, Cato AM, Smith AD. Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol. 1997; 94: 6-15.
  42. Nagy Z, Esiri MM, Smith AD. Expression of cell divi- sion markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol. 1997; 93: 294-300.
  43. Nagy ZS, Esiri MM. Apoptosis-related protein expres- sion in the hippocampus in Alzheimer's disease. Neurobiol Aging. 1997; 18: 565-71.
  44. Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol. 2001; 101: 305-10.
  45. Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB. On the question of apoptosis in the parkin- sonian substantia nigra. Acta neuropathologica. 1997; 93: 105-8.
  46. Jellinger KA. Cell death mechanisms in neurodegenera- tion. J Cel Mol Med. 2001; 5: 1-17.
  47. Massague J. G1 cell-cycle control and cancer. Nature 2004; 432: 298-306.
  48. Suzuki T, Oishi M, Marshak DR, Czernik AJ, Nairn AC, Greengard P. Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J. 1994; 13: 1114-22.
  49. Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer dis- ease. Proc Natl Acad Sci USA. 1985; 82: 4531-4.
  50. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3α regu- lates production of Alzheimer's disease amyloid-beta pep- tides. Nature 2003; 423: 435-9.
  51. Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. Journal of neuroscience the official Journal of the Society for Neuroscience 1998; 18: 2801-7.
  52. Katchanov J, Harms C, Gertz K, Hauck L, Waeber C, Hirt L, Priller J, von Harsdorf R, Bruck W, Hortnagl H, Dirnagl U, Bhide PG, Endres M. Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J Neurosci. 2001; 21: 5045-53.
  53. Bossenmeyer-Pourie C, Chihab R, Schroeder H, Daval JL. Transient hypoxia may lead to neuronal proliferation in the developing mammalian brain: from apoptosis to cell cycle completion. Neuroscience 1999; 91: 221-31.
  54. Smith MZ, Nagy Z, Esiri MM. Cell cycle-related protein expression in vascular dementia and Alzheimer's disease. Neurosci Lett. 1999; 271: 45-8.
  55. Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, Joachim C, Litchfield S, Barnetson L, Smith AD. The effects of additional pathology on the cog- nitive deficit in Alzheimer disease. J Neuropathol Exp Neurol. 1997; 56: 165-70.
  56. Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999; 354: 919-20.
  57. Zhu X, Raina AK, Perry G, Smith MA. Alzheimer's dis- ease: the two-hit hypothesis. Lancet Neurol. 2004; 3: 219-26.
  58. Nagy Z. Cell cycle regulatory failure in neurones: causes and consequences. Neurobiol Aging 2000; 21: 761-9.
  59. Nagy ZS, Smith MZ, Esiri MM, Barnetson L, Smith AD. Hyperhomocysteinaemia in Alzheimer's disease and expression of cell cycle markers in the brain. J Neurol Neurosurg Psychiatry 2000; 69: 565-6.
  60. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homo- cysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998; 55: 1449-55.
  61. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 2003; 26: 137-46.
  62. Arendt T, Holzer M, Gartner U. Neuronal expression of cycline dependent kinase inhibitors of the INK4 fam- ily in Alzheimer's disease. Journal of Neural Transmis- sion Vienna, Austria 1996 1998; 105: 949-60.
  63. Zhu X, McShea A, Harris PL, Raina AK, Castellani RJ, Funk JO, Shah S, Atwood C, Bowen R, Bowser R, Morelli L, Perry G, Smith MA. Elevated expres- sion of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease. J Neurosci Res. 2004; 75: 698-703.
  64. Ogawa O, Lee HG, Zhu X, Raina A, Harris PL, Castellani RJ, Perry G, Smith MA. Increased p27, an essential component of cell cycle control, in Alzheimer's disease. Aging Cell 2003; 2: 105-10.
  65. Nagy Z, Hindley NJ, Braak H, Braak E, Yilmazer-Hanke DM, Schultz C, Barnetson L, Jobst KA, Smith AD. Relationship between clin- ical and radiological diagnostic criteria for Alzheimer's disease and the extent of neu- ropathology as reflected by 'stages': a prospective study. Dement Geriatr Cogn Disord. 1999; 10: 109-14.
  66. Nagy Z, Hindley NJ, Braak H, Braak E, Yilmazer-Hanke DM, Schultz C, Barnetson L, King EM, Jobst KA, Smith AD. The progression of Alzheimer's disease from limbic regions to the neo- cortex: clinical, radiological and pathological rela- tionships. Dement Geriatr Cogn Disord. 1999; 10: 115-20.
  67. Burke WJ, McLaughlin JR, Chung HD, Gillespie KN, Grossberg GT, Luque FA, Zimmerman J. Occurrence of cancer in Alzheimer and elderly control patients: an epidemiologic necropsy study. Alzheimer Dis Assoc Disord. 1994; 8: 22-8.
  68. Nagy Z, Combrinck M, Budge M, McShane R. Cell cycle kinesis in lymphocytes in the diagnosis of Alzheimer's disease. Neurosci Lett. 2002; 317: 81-4.
  69. Popescu NC. Comprehensive genetic analysis of can- cer cells. J Cell Mol Med. 2000; 4: 151-63.

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Authors
Nagy, Z.
Affiliations
University of Birmingham (GB)
Corresponding author
Nagy, Zsuzsanna
ORCID
Nagy, Zsuzsanna
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2005-07
Volume
9
Issue
3
Pages
531-541
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/j.1582-4934.2005.tb00485.x
PMC
PMC6741636
OpenAlex
W1991108713
Cited by
56
References
6
Citations by year
2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2013: 2 · 2012: 3
FWCI
0.96
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 3714 d)
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, pathogenesis, unifying hypothesis, neurodegeneration, amyloid hypothesis, tau hypothesis, Alzheimer's disease treatment, Alzheimer's disease diagnosis
MeSH terms
Alzheimer Disease, Cell Cycle, Cell Division, Humans, Models, Neurological, Neurons, Neurofibrillary Tangles

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