Amyloid ?1-42 (A?1-42) Induces the CDK2-Mediated Phosphorylation of Tau through the Activation of the mTORC1 Signaling Pathway While Promoting Neuronal Cell Death.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid ?1-42 (A?) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how A? induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of A? with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer A? (5 ?M) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. A? induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). A? signaling through ROS production is uniquely mediated by the activation of PI3K/Akt, which is in turn required for mammalian target of rapamycin complex 1 (mTORC1) phosphorylation. mTORC1 activated by A? further increased the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a binding protein (4E-BP1) and p70S6K1 to stimulate the HIF1? synthesis responsible for the induction of cyclinD1/cyclin-dependent kinase 4 (CDK4) and cyclinE/CDK2, whereas it significantly attenuated the activation of autophagy. A? distinctively induced the CDK2-mediated phosphorylation of tau, which is responsible for microtubule destabilization in promoting neuronal apoptosis. In mouse hippocampal primary neurons, the apoptotic cell death induced by A? is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that A? efficiently stimulates the mTORC1 signaling pathway to facilitate HIF1? synthesis and autophagy inhibition to promote the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for microtubule destabilization-mediated neuronal apoptosis.

SUBMITTER: Lee KH 

PROVIDER: S-EPMC5522873 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature