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FoxO3a is activated and executes neuron death via Bim in response to ?-amyloid.

ABSTRACT: The molecules that mediate death of selective neurons in Alzheimer's disease (AD) are mostly unknown. The Forkhead transcription factor FoxO3a has emerged as an important mediator of cell fate including apoptosis. When phosphorylated by Akt, it is localized in the cytosol as an inactive complex bound with 14-3-3 protein. For activation and localization of FoxO3a in the nucleus, further modifications are required, such as phosphorylation by mammalian sterile 20-like kinase 1 (MST1) and arginine methylation by protein arginine methyltransferase1. We report here that Akt-mediated phosphorylation of FoxO3a is diminished in neurons exposed to oligomeric ?-amyloid (A?), in vitro and in vivo. We also find that oligomeric A? activates FoxO3a by MST1 phosphorylation and arginine methylation in primary cultures of hippocampal and cortical neurons. Moreover, FoxO3a translocates from the cytosol to nucleus in cultured neurons in response to A?. Most importantly, the nuclear redistribution of FoxO3a is significantly increased in A?-overexpressing A?PPswe-PS1dE9 mice and A?-infused rat brains. We further find that FoxO3a is essential for loss of neurons and neural networks in response to A?. Recent reports implicate Bim, a pro-apoptotic member of Bcl-2 family, in neuron death in AD, as a key target of this transcription factor. We show that Bim is a direct target of FoxO3a in A?-treated neurons. Our findings thus indicate that FoxO3a is activated, translocated to the nucleus and mediates neuron death via Bim in response to A? toxicity.

SUBMITTER: Sanphui P

PROVIDER: S-EPMC3674357 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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FoxO3a is activated and executes neuron death via Bim in response to β-amyloid.

Sanphui P P Biswas S C SC

Cell death & disease 20130509

The molecules that mediate death of selective neurons in Alzheimer's disease (AD) are mostly unknown. The Forkhead transcription factor FoxO3a has emerged as an important mediator of cell fate including apoptosis. When phosphorylated by Akt, it is localized in the cytosol as an inactive complex bound with 14-3-3 protein. For activation and localization of FoxO3a in the nucleus, further modifications are required, such as phosphorylation by mammalian sterile 20-like kinase 1 (MST1) and arginine m ...[more]

PMID: 23661003

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Project description:We reported that zinc neurotoxicity, a key mechanism of ischemic neuronal death, was mediated by poly ADP-ribose polymerase (PARP) over-activation following NAD(+)/ATP depletion in cortical cultures. Because AMP-activated protein kinase (AMPK) can be activated by ATP depletion, and AMPK plays a key role in excitotoxicity and ischemic neuronal death, we examined whether AMPK could be involved in zinc neurotoxicity in mouse cortical neuronal cultures.Compound C, an AMPK inhibitor, significantly attenuated zinc-induced neuronal death. Activation of AMPK was detected beginning 2 h after a 10-min exposure of mouse cortical neurons to 300 ?M zinc, although a significant change in AMP level was not detected until 4 h after zinc treatment. Thus, AMPK activation might not have been induced by an increase in intracellular AMP in zinc neurotoxicity. Furthermore, we observed that liver kinase B1 (LKB1) but not Ca(2+)/calmodulin-dependent protein kinase kinase ? (CaMKK?), was involved in AMPK activation. Although STO-609, a chemical inhibitor of CaMKK?, significantly attenuated zinc neurotoxicity, zinc-induced AMPK activation was not affected, which suggested that CaMKK? was not involved in AMPK activation. Knockdown of LKB1 by siRNA significantly reduced zinc neurotoxicity, as well as zinc-induced AMPK activation, which indicated a possible role for LKB1 as an upstream kinase for AMPK activation. In addition, mRNA and protein levels of Bim, a pro-apoptotic Bcl-2 family member, were noticeably increased by zinc in an AMPK-dependent manner. Finally, caspase-3 activation in zinc-induced neuronal death was mediated by LKB1 and AMPK activation.The results suggested that AMPK mediated zinc-induced neuronal death via up-regulation of Bim and activation of caspase-3. Rapid activation of AMPK was detected after exposure of cortical neuronal cultures to zinc, which was induced by LKB1 activation but not increased intracellular AMP levels or CaMKK? activation. Hence, blockade of AMPK in the brain may protect against zinc neurotoxicity, which is likely to occur after acute brain injury.

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FoxO3a is activated and executes neuron death via Bim in response to ?-amyloid.

Publications

FoxO3a is activated and executes neuron death via Bim in response to β-amyloid.

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