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

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

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

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 (A) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble A species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to A 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 A monomer or A 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 A oligomer treated neurons exhibit elevated levels of activated Akt and mTOR (mammalian Target Of Rapamycin) and that PI3K, Akt or mTOR inhibitors blocked A oligomer-induced neuronal CCEs. Taken together, these results demonstrate that A oligomer-based induction of neuronal CCEs involve the PI3K-Akt-mTOR pathway.

Original languageEnglish (US)
Article number14
JournalMolecular Neurodegeneration
Volume4
Issue number1
DOIs
StatePublished - Apr 13 2009

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Sirolimus
Phosphatidylinositol 3-Kinases
Cell Cycle
Neurons
Amyloid beta-Protein Precursor
Alzheimer Disease
Amyloid

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

The PI3K-Akt-mTOR pathway regulates a oligomer induced neuronal cell cycle events. / Bhaskar, Kiran; Miller, Megan; Chludzinski, Alexandra; Herrup, Karl; Zagorski, Michael; Lamb, Bruce T.

In: Molecular Neurodegeneration, Vol. 4, No. 1, 14, 13.04.2009.

Research output: Contribution to journalArticle

Bhaskar, Kiran ; Miller, Megan ; Chludzinski, Alexandra ; Herrup, Karl ; Zagorski, Michael ; Lamb, Bruce T. / The PI3K-Akt-mTOR pathway regulates a oligomer induced neuronal cell cycle events. In: Molecular Neurodegeneration. 2009 ; Vol. 4, No. 1.
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