Skip to main content

Advertisement

SpringerLink
Log in

Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the intracellular accumulation of highly phosphorylated tau protein, the extracellular formation of amyloid plaques and a significant loss of neurons. Recent evidence suggests that neuronal death in AD involves an aborted attempt of cells to re-enter the cell cycle. To study the effect of amyloid deposits on cell cycle related events in vivo, the expression of cell cycle markers was examined by immunohistochemistry in amyloid precursor protein (APP) transgenic mice (APP23 mice, Swedish double mutation). Aβ deposition in APP23 mice is associated with prominent gliosis that is characterized by an astrocytic expression of cyclins D1, E and B1 as well as the nuclear translocation of cyclin-dependent protein kinase 4. However, amyloid plaque formation is not accompanied by significant changes in the neuronal expression of cyclins or cyclin-dependent kinase inhibitors. It is concluded, therefore, that in contrast to AD, amyloid pathology in APP23 mice is not associated with changes in the expression of cell cycle markers in neurons. The results support the assumption that the neuronal re-expression of cell cycle components in AD is not a consequence of Aβ formation and deposition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. Arendt T, Rödel L, Gärtner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport 7:3047–3049

    CAS  PubMed  Google Scholar 

  2. Arendt T, Holzer M, Gärtner U (1998) Neuronal expression of cyclin dependent kinase inhibitors of the INK4 family in Alzheimer's disease. J Neural Transm 105:949–960

    Article  CAS  PubMed  Google Scholar 

  3. Arendt T, Holzer M, Gärtner U, Brückner MK (1998) Aberrancies in signal transduction and cell cycle related events in Alzheimer's disease. J Neural Transm Suppl 54:147–158

    CAS  PubMed  Google Scholar 

  4. Arendt T, Holzer M, Stöbe A, Gärtner U, Lüth HJ, Brückner MK, Ueberham U (2000) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death. Ann NY Acad Sci 920:249–255

    CAS  PubMed  Google Scholar 

  5. Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS (2001) C-terminal fragment of amyloid precursor protein induces astrocytosis. J Neurochem 78:109–120

    Article  CAS  PubMed  Google Scholar 

  6. Bondolfi L, Calhoun M, Ermini F, Kuhn HG, Wiederhold KH, Walker L, Staufenbiel M, Jucker M (2002) Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J Neurosci 22:515–522

    CAS  PubMed  Google Scholar 

  7. Bornemann KD, Staufenbiel M (2000) Transgenic mouse models of Alzheimer's disease. Ann NY Acad Sci 908:260–266

    CAS  PubMed  Google Scholar 

  8. Bornemann KD, Wiederhold KH, Pauli C, Ermini F, Stalder M, Schnell L, Sommer B, Jucker M, Staufenbiel M (2001) Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am J Pathol 158:63–73

    CAS  PubMed  Google Scholar 

  9. Busciglio J, Yeh J, Yankner BA (1993) Beta-Amyloid neurotoxicity in human cortical culture is not mediated by excitotoxins. J Neurochem 61:1565–1568

    CAS  PubMed  Google Scholar 

  10. Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M (1998) Neuron loss in APP transgenic mice. Nature 395:755–756

    Google Scholar 

  11. Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, Canonico PL, Nicoletti F, Sortino MA (1999) Mitotic signaling by beta-amyloid causes neuronal death. FASEB J 13:2225–2234

    CAS  PubMed  Google Scholar 

  12. Fischer SJ, McDonald ES, Gross L, Windebank AJ (2001) Alterations in cell cycle regulation underlie cisplatin induced apoptosis of dorsal root ganglion neurons in vivo. Neurobiol Dis 8:1027–1035

    Article  CAS  PubMed  Google Scholar 

  13. Freeman RS, Estus S, Johnson EM Jr (1994) Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of cyclin D1 during programmed cell death. Neuron 12:343–355

    CAS  Google Scholar 

  14. Games D, Adams D, Alessandrini R, et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    CAS  PubMed  Google Scholar 

  15. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA (1998) Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med 4:827–831

    CAS  PubMed  Google Scholar 

  16. Hsiao K (1998) Transgenic mice expressing Alzheimer amyloid precursor proteins. Exp Gerontol 33:883–889

    Article  CAS  PubMed  Google Scholar 

  17. Hu J, Akama KT, Krafft GA, Chromy BA, Van Eldik LJ (1998) Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res 785:195–206

    Article  CAS  PubMed  Google Scholar 

  18. Husseman JW, Nochlin D, Vincent I (2000) Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging 21:815–828

    Article  CAS  PubMed  Google Scholar 

  19. Ino H, Chiba T (2001) Cyclin-dependent kinase 4 and cyclin D1 are required for excitotoxin-induced neuronal cell death in vivo. J Neurosci 21:6086–6094

    CAS  PubMed  Google Scholar 

  20. Jin K, Nagayama T, Chen J, Stetler AR, Kawaguchi K, Simon RP, Graham SH (1999) Molecular cloning of a cell cycle regulation gene cyclin H from ischemic rat brain: expression in neurons after global cerebral ischemia. J Neurochem 73:1598–1608

    Article  CAS  PubMed  Google Scholar 

  21. 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 (2001) Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J Neurosci 21:5045–5053

    CAS  PubMed  Google Scholar 

  22. Kaya SS, Mahmood A, Li Y, Yavuz E, Chopp M (1999) Expression of cell cycle proteins (cyclin D1 and cdk4) after controlled cortical impact in rat brain. J Neurotrauma 16:1187–1196

    CAS  PubMed  Google Scholar 

  23. Lamb BT, Bardel KA, Kulnane LS, Anderson JJ, Holtz G, Wagner SL, Sisodia SS, Hoeger EJ (1999) Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice. Nat Neurosci 2:695–697

    Article  CAS  PubMed  Google Scholar 

  24. Legrier ME, Ducray A, Propper A, Kastner A (2001) Region-specific expression of cell cycle inhibitors in the adult brain. Neuroreport 12:3127–3131

    CAS  PubMed  Google Scholar 

  25. Li J, Meyer AN, Donoghue DJ (1997) Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation. Proc Natl Acad Sci USA 94:502–507

    CAS  PubMed  Google Scholar 

  26. Li V, Kelly K, Schrot R, Langan TJ (1996) Cell cycle kinetics and commitment in newborn, adult, and tumoral astrocytes. Brain Res Dev Brain Res 96:138–147

    CAS  PubMed  Google Scholar 

  27. Li Y, Chopp M, Powers C (1997) Granule cell apoptosis and protein expression in hippocampal dentate gyrus after forebrain ischemia in the rat. J Neurol Sci 150:93–102

    Article  CAS  PubMed  Google Scholar 

  28. Liu DX, Greene LA (2001) Neuronal apoptosis at the G1/S cell cycle checkpoint. Cell Tissue Res 305:217–228

    Article  CAS  PubMed  Google Scholar 

  29. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW (1993) Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA 90:7951–7955

    CAS  PubMed  Google Scholar 

  30. Lüth HJ, Holzer M, Gärtner U, Staufenbiel M, Arendt T (2001) Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology. Brain Res 913:57–67

    Article  PubMed  Google Scholar 

  31. Malchiodi-Albedi F, Domenici MR, Paradisi S, Bernardo A, Ajmone-Cat MA, Minghetti L (2001) Astrocytes contribute to neuronal impairment in beta A toxicity increasing apoptosis in rat hippocampal neurons. Glia 34:68–72

    Article  CAS  PubMed  Google Scholar 

  32. Matsunaga Y (2000) Expression of cyclin E in postmitotic cells in the central nervous system. Kokubyo Gakkai Zasshi 67:169–181

    CAS  PubMed  Google Scholar 

  33. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) Beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12:376–389

    CAS  PubMed  Google Scholar 

  34. McShea A, Harris PL, Webster, 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

    Google Scholar 

  35. Milton NG (2002) The amyloid-beta peptide binds to cyclin B1 and increases human cyclin-dependent kinase-1 activity. Neurosci Lett 322:131–133

    Article  CAS  PubMed  Google Scholar 

  36. Miyajima M, Nornes HO, Neuman T (1995) Cyclin E is expressed in neurons and forms complexes with cdk5. Neuroreport 6:1130–1132

    CAS  PubMed  Google Scholar 

  37. Miyazawa K, Himi T, Garcia V, Yamagishi H, Sato S, Ishizaki Y (2000) A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J Neurosci 20:5756–5763

    CAS  PubMed  Google Scholar 

  38. Nagahama H, Hatakeyama S, Nakayama K, Nagata M, Tomita K, Nakayama K (2001) Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 during mouse development. Anat Embryol (Berl) 203:77–87

    Google Scholar 

  39. Nagy Z, Esiri MM, Cato AM, Smith AD (1997) Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol 94:6–15

    Article  CAS  PubMed  Google Scholar 

  40. Oka T, Kubo T, Enokido Y, Hatanaka H (1996) Expression of cyclin A decreases during neuronal apoptosis in cultured rat cerebellar granule neurons. Brain Res Dev Brain Res 97:96-106

    Article  CAS  PubMed  Google Scholar 

  41. Pike CJ, Cummings BJ, Monzavi R, Cotman CW (1994) Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease. Neuroscience 63:517–531

    Article  CAS  PubMed  Google Scholar 

  42. Pines J, Hunter T (1991) Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol 115:1–17

    CAS  PubMed  Google Scholar 

  43. Postigo JA, Werf YD van der, Korf HJ, Krugers HJ (1998) Altered expression of the cell cycle regulatory protein cyclin D1 in the rat dentate gyrus after adrenalectomy-induced granular cell loss. Neurosci Lett 241:107–110

    Article  CAS  PubMed  Google Scholar 

  44. Prosperi E, Stivala LA, Scovassi AI, Bianchi L (1997) Cyclins: relevance of subcellular localization in cell cycle control. Eur J Histochem 41:161–168

    CAS  Google Scholar 

  45. Richter JD (2001) Think globally, translate locally: what mitotic spindles and neuronal synapses have in common. Proc Natl Acad Sci USA 98:7069–7071

    Article  CAS  PubMed  Google Scholar 

  46. Sgambato A, Cittadini A, Faraglia B, Weinstein IB (2000) Multiple functions of p27(Kip1) and its alterations in tumor cells: a review. J Cell Physiol 183:18–27

    Article  CAS  PubMed  Google Scholar 

  47. Shambaugh GE 3rd, Haines GK 3rd, Koch A, Lee EJ, Zhou J, Pestell R (2000) Immunohistochemical examination of the INK4 and Cip inhibitors in the rat neonatal cerebellum: cellular localization and the impact of protein calorie malnutrition. Brain Res 855:11–22

    Article  CAS  PubMed  Google Scholar 

  48. Sherr C J (1995) D-type cyclins. Trends Biochem Sci 20:187–190

    Article  CAS  PubMed  Google Scholar 

  49. Shirvan A, Ziv I, Machlin T, Zilkha-Falb R, Melamed E, Barzilai A (1997) Two waves of cyclin B and proliferating cell nuclear antigen expression during dopamine-triggered neuronal apoptosis. J Neurochem 69:539–549

    CAS  PubMed  Google Scholar 

  50. Shirvan A, Ziv I, Zilkha-Falb R, Machlyn T, Barzilai A, Melamed E (1998) Expression of cell cycle-related genes during neuronal apoptosis: is there a distinct pattern? Neurochem Res 23:767–777

    Article  CAS  PubMed  Google Scholar 

  51. Small DL, Monette R, Comas T, Fournier M, Morley P (1999) Loss of cyclin D1 in necrotic and apoptotic models of cortical neuronal degeneration. Brain Res 842:376–383

    Article  CAS  PubMed  Google Scholar 

  52. Small DL, Monette R, Fournier MC, Zurakowski B, Fiander H, Morley P (2001) Characterization of cyclin D1 expression in a rat global model of cerebral ischemia. Brain Res 900:26–37

    Article  CAS  PubMed  Google Scholar 

  53. Sommer B, Sturchler-Pierrat C, Abramowski D, Wiederhold KH, Calhoun M, Jucker M, Kelly P, Staufenbiel M (2000) Transgenic approaches to model Alzheimer's disease. Rev Neurosci 11:47–51

    CAS  PubMed  Google Scholar 

  54. Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 154:1673–1684

    CAS  PubMed  Google Scholar 

  55. Stalder M, Deller T, Staufenbiel M, Jucker M (2001) 3D-Reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid. Neurobiol Aging 22:427–434

    Article  CAS  PubMed  Google Scholar 

  56. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292

    Article  CAS  Google Scholar 

  57. Tamaru T, Trigun SK, Okada M, Nakagawa H (1993) Identification of cells expressing a D type G1 cyclin in matured brain: implication for its role in neuronal function. Neurosci Lett 153:169–172

    Article  CAS  PubMed  Google Scholar 

  58. Thatcher JD, McBride B, Katula KS (1995) Promoter binding factors regulating cyclin B transcription in the sea urchin embryo. DNA Cell Biol 14:869–881

    CAS  PubMed  Google Scholar 

  59. Timsit S, Rivera S, Ouaghi P, Guischard F, Tremblay E, Ben-Ari Y, Khrestchatisk M (1999). Increased cyclin D1 in vulnerable neurons in the hippocampus after ischaemia and epilepsy: a modulator of in vivo programmed cell death? Eur J Neurosci 11:263–278

    Article  CAS  PubMed  Google Scholar 

  60. Van Lookeren Campagne M, Gill R (1998) Cell cycle-related gene expression in the adult rat brain: selective induction of cyclin G1 and p21Waf1/Cip1 in neurons following focal cerebral ischemia. Neuroscience 84:1097–1112

    PubMed  Google Scholar 

  61. 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

    CAS  PubMed  Google Scholar 

  62. Watanabe G, Pena P, Shambaugh GE 3rd, Haines GK 3rd, Pestell RG (1998) Regulation of cyclin dependent kinase inhibitor proteins during neonatal cerebellar development. Brain Res Dev Brain Res 108:77–87

    Article  CAS  PubMed  Google Scholar 

  63. Wiessner C, Brink I, Lorenz P, Neumann-Haefelin T, Vogel P, Yamashita K (1996) Cyclin D1 messenger RNA is induced in microglia rather than neurons following transient forebrain ischaemia. Neuroscience 72:947–958

    Article  CAS  PubMed  Google Scholar 

  64. Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K (2000) Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol Aging 21:797–806

    Article  CAS  PubMed  Google Scholar 

  65. Yang J, Kornbluth S (1999) All aboard the cyclin train: subcellular trafficking of cyclins and their CDK partners. Trends Cell Biol 9:207–210

    Article  CAS  PubMed  Google Scholar 

  66. Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245:417–420

    CAS  PubMed  Google Scholar 

  67. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282

    Google Scholar 

  68. Zindy F, Soares H, Herzog KH, Morgan J, Sherr CJ, Roussel MF (1997) Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ 8:1139–1150

    CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by grants from the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) at the University of Leipzig (01KS9504, Project C1); the European Commission (QLK6-CT-1999-02112) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Neuroanatomy, Paul Flechsig Institute of Brain Research, University of Leipzig, Jahnallee 59, 04109, Leipzig, Germany

    Ulrich Gärtner, Martina K. Brückner, Sabine Krug, Stefanie Schmetsdorf & Thomas Arendt

  2. Central Nervous System Research, Novartis Pharma Inc., 4002, Basel, Switzerland

    Matthias Staufenbiel

Authors
  1. Ulrich Gärtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina K. Brückner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabine Krug
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefanie Schmetsdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Staufenbiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Arendt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Gärtner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gärtner, U., Brückner, M.K., Krug, S. et al. Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons. Acta Neuropathol 106, 535–544 (2003). https://doi.org/10.1007/s00401-003-0760-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-003-0760-8

Keywords

Search

Navigation