Aβ oligomers induce neuronal cell cycle events in Alzheimer's disease

Nicholas H. Varvel, Kiran Bhaskar, Anita R. Patil, Sanjay W. Pimplikar, Karl Herrup, Bruce T. Lamb

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Neurons subject to degeneration in Alzheimer's disease (AD) exhibit evidence of re-entry into a mitotic cell cycle even before the development of substantial AD brain pathology. In efforts to identify the initiating factors underlying these cell cycle events (CCEs), we have characterized the appearance of the neuronal CCEs in the genomic-based R1.40 transgenic mouse model of AD. Notably, R1.40 mice exhibit neuronal CCEs in a reproducible temporal and spatial pattern that recapitulates the neuronal vulnerability seen in human AD. Neuronal CCEs first appear at 6 months in the frontal cortex layers II/III. This is 6-8 months before detectable amyloid β (Aβ) deposition, suggesting that specific amyloid precursor protein (APP) processing products are responsible for the induction of neuronal CCEs. Furthermore, a reduction in the levels of Aβ (achieved by shifting the genetic background from C57BL/6 to the DBA/2 mouse strain) dramatically delays the appearance of neuronal CCEs. More significantly, elimination of β-secretase activity blocks the appearance of CCEs, providing direct genetic evidence that the amyloidogenic processing of APP is required for the induction of CCEs. Finally, in vitro preparations of oligomeric, but not monomeric, Aβ induce DNA synthesis in dissociated cortical neurons, and this response is blocked by antioligomer specific antibodies. Together, our data suggest that low molecular weight aggregates of Aβ induce neuronal cell cycle re-entry in mouse models of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)10786-10793
Number of pages8
JournalJournal of Neuroscience
Volume28
Issue number43
DOIs
StatePublished - Oct 22 2008

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Keywords

  • APP
  • Alzheimer's disease
  • Cyclin A
  • Neuronal cell cycle
  • Transgenic mice
  • β-amyloid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Varvel, N. H., Bhaskar, K., Patil, A. R., Pimplikar, S. W., Herrup, K., & Lamb, B. T. (2008). Aβ oligomers induce neuronal cell cycle events in Alzheimer's disease. Journal of Neuroscience, 28(43), 10786-10793. https://doi.org/10.1523/JNEUROSCI.2441-08.2008