Research article

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

Kiran Bhaskar¹ , Megan Miller² , Alexandra Chludzinski³ , Karl Herrup⁴ , Michael Zagorski² and Bruce T Lamb^1,3,5,6

¹  Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH, USA

²  Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA

³  Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

⁴  Department of Cell Biology and Neuroscience, Rutgers University, Piscataway NJ, USA

⁵  Department of Genetics, Case Western Reserve University, Cleveland, OH, USA

⁶  Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA

author email corresponding author email

Molecular Neurodegeneration 2009, 4:14doi:10.1186/1750-1326-4-14

Published:	16 March 2009

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 (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.