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The PI3K-Akt-mTOR pathway regulates Aβ oligomer induced neuronal cell cycle events

By Kiran Bhaskar, Megan Miller, Alexandra Chludzinski, Karl Herrup, Michael Zagorski and Bruce T Lamb


Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Aβ) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Aβ species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to Aβ oligomers, but not monomers or fibrils, results in the retraction of neuronal processes, and induction of CCEs in a concentration dependent manner. Retraction of neuronal processes correlated with the induction of CCEs and the Aβ monomer or Aβ fibrils showed only minimal effects. In addition, we provide evidence that induction of neuronal CCEs are autonomous to primary neurons cultured from the R1.40 mice. Finally, our results also demonstrate that Aβ oligomer treated neurons exhibit elevated levels of activated Akt and mTOR (mammalian Target Of Rapamycin) and that PI3K, Akt or mTOR inhibitors blocked Aβ oligomer-induced neuronal CCEs. Taken together, these results demonstrate that Aβ oligomer-based induction of neuronal CCEs involve the PI3K-Akt-mTOR pathway

Topics: Research Article
Publisher: BioMed Central
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Provided by: PubMed Central

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  1. (2007). A: The mTOR pathway as a potential target for the development of therapies against neurological disease. Drug News Perspect
  2. (2000). AB: beta-Amyloid(1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.
  3. (2001). Alzheimer's disease: genes, proteins, and therapy. Physiol Rev
  4. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med
  5. (2004). Angela Sortino M: Beta-amyloid-activated cell cycle in SH-SY5Y neuroblastoma cells: correlation with the MAP kinase pathway.
  6. (2000). Annaert W: Proteolytic processing and cell biological functions of the amyloid precursor protein.
  7. (2007). Anwyl R: Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptideinduced dysfunction. Biochem Soc Trans
  8. (2004). Ashe KH, et al.: Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron
  9. (2006). Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature
  10. (2007). BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.
  11. (2005). Bruning JC: The role of insulin receptor signaling in the brain. Trends Endocrinol Metab
  12. (2008). Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Abeta1–42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease.
  13. (2005). Cellcycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms.
  14. (2002). Cole G: Alzheimer disease. JAMA
  15. (1988). Crouch SR: Spectrochemical Analysis
  16. (2005). CW: The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation. Curr Top Med Chem
  17. (2007). DV: PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol
  18. (2003). et al.: Role of protein kinase B in Alzheimer's neurofibrillary pathology. Acta Neuropathol
  19. (2007). F: The nature of the cell cycle in neurons: focus on a "noncanonical" pathway of DNA replication causally related to death. Biochim Biophys Acta
  20. (2006). Feany MB: TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol
  21. (2002). Fodero LR: Cholinergic regulation of synaptic plasticity as a therapeutic target in Alzheimer's disease.
  22. (2008). G: Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis
  23. (2005). Greengard P: Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci
  24. (2000). Herrup K: Betaamyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol Aging
  25. (2007). Herrup K: Cell division in the CNS: protective response or lethal event in post-mitotic neurons? Biochim Biophys Acta
  26. (2005). Herrup K: Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation.
  27. (2006). Herrup K: Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models.
  28. (2003). Herrup K: Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease.
  29. (2000). I: Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging
  30. (2002). JW: Signaling events in amyloid betapeptide-induced neuronal death and insulin-like growth factor I protection.
  31. (2002). LaDu MJ: Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability.
  32. (2008). Lamb BT: Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
  33. (2005). Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain.
  34. (1999). Membraneanchored aspartyl protease with Alzheimer's disease betasecretase activity. Nature
  35. (2004). MG: Sorting out the driving forces for parallel and antiparallel alignment in the abeta peptide fibril structure.
  36. (2007). Monoclonal antibodies that target pathological assemblies of Abeta.
  37. (2005). mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease.
  38. (2007). Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta
  39. (2005). O'Neill C: Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology.
  40. (1991). Oster-Granite ML: Expression of the amyloid precursor protein gene in mouse oocytes and embryos.
  41. (1980). PR: Part II: Techniques for the study of biological structure and function 1st edition.
  42. (2003). R: M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer's disease: implications in future therapy.
  43. (2003). Rowinsky EK: The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther
  44. (2005). Selkoe DJ: Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.
  45. (2000). Selkoe DJ: The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry
  46. (2001). SL: A gene trap insertion reveals that amyloid precursor protein expression is a very early event in murine embryogenesis. Dev Genes Evol
  47. (2003). SL: Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell
  48. (2008). Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res
  49. (2008). Suppiramaniam V: Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol
  50. (1997). Teplow DB: Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate.
  51. (2001). Teplow DB: Amyloid beta-protein oligomerization: prenucleation interactions revealed by photoinduced cross-linking of unmodified proteins.
  52. (2002). Trommer BL: Soluble oligomers of beta amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res
  53. (2008). Two motifs within the tau microtubule-binding domain mediate its association with the hsc70 molecular chaperone.
  54. (1989). Very mild senile dementia of the Alzheimer type. I. Clinical assessment. Arch Neurol
  55. (2007). WL: Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease.
  56. (2008). WL: Amyloid beta oligomers induce impairment of neuronal insulin receptors.
  57. (2008). WL: Why Alzheimer's is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging
  58. (1994). Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res
  59. (2008). XY: Leptin increases adult hippocampal neurogenesis in vivo and in vitro.

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