Neuronal cell cycle re-entry mediates Alzheimer disease-type changes

Andrew McShea, Hyoung gon Lee, Robert B. Petersen, Gemma Casadesus, Inez Vincent, Nancy J. Linford, Jens Oliver Funk, Robert A. Shapiro, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

Abstract

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

Original languageEnglish
Pages (from-to)467-472
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1772
Issue number4
DOIs
StatePublished - Apr 2007

Keywords

  • Alzheimer disease
  • Cell cycle
  • Phosphorylation
  • Tau

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