AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation
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Adenosine monophosphate-activated protein kinase (AMPK) is a member of metabolite-sensing kinase family that plays important roles in responses of muscle cells to metabolic stress. AMPK is a heterotrimer of a catalytic α subunit (α1 or α2), and β (β1 or β2) and γ (γ1 or γ2) subunits. Because the brain has a high metabolic rate and is sensitive to changes in the supply of glucose and oxygen, we investigated the expression of AMPK in rat embryonic and adult brain and its role in modifying neuronal survival under conditions of cellular stress. We report that catalytic (α1 and α2) and noncatalytic (β2 and γ1) subunits of AMPK are present at high levels in embryonic hippocampal neurons in vivo and in cell culture. In the adult rat brain, the catalytic subunits α1 and α2 are present in neurons throughout the brain. The AMPK-activating agent AICAR protected hippocampal neurons against death induced by glucose deprivation, chemical hypoxia, and exposure to glutamate and amyloid β-peptide. Suppression of levels of the AMPK α1 and α2 subunits using antisense technology resulted in enhanced neuronal death following glucose deprivation, and abolished the neuroprotective effect of AICAR. These findings suggest that AMPK can protect neurons against metabolic and excitotoxic insults relevant to the pathogenesis of several different neurodegenerative conditions.
Index EntriesAICAR Alzheimer AMPK amyloid antisense apoptosis glutamate hippocampus ischemia
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- Davies, S. P., Helps, N. R., Cohen, P. T., and Hardie, D. G. (1995) 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421–425.PubMedCrossRefGoogle Scholar
- Hawley, S. A., Davison, M., Woods, A., Davies, S. P., Beri, R. K., Carling, D., and Hardie, D. G. (1996) Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271, 27,879–27,887.Google Scholar
- Kudo, N., Gillespie, J. G., Kung, L., Witters, L. A., Schulz, R., Clanachan, A. S., and Lopaschuk, G. D. (1996) Characterization of 5′AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim. Biophys. Acta 1301, 67–75.PubMedGoogle Scholar
- Mattson, M. P., Lovell, M. A., Furukawa, K., and Markesbery, W. R. (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751.PubMedCrossRefGoogle Scholar
- Mattson, M. P., Goodman, Y., Luo, H., Fu, W., and Furukawa, K. (1997) Activation of NF-κB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J. Neurosci. Res. 49, 681–697.PubMedCrossRefGoogle Scholar
- Smith-Swintosky, V. L., Pettigrew, L. C., Sapolsky, R. M., Phares, C., Craddock, S. D., Brooke, S. M., and Mattson, M. P. (1996) Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures. J. Cereb. Blood Flow Metab. 16, 585–598.PubMedCrossRefGoogle Scholar
- Stapleton, D., Gao, G., Michell, B. J., Widmer, J., Mitchelhill, K., Teh, T., et al. (1994) Mammalian 5′-AMP-activated protein kinase non-catalytic subunits are homologs of proteins that interact with yeast Snf1 protein kinase. J. Biol. Chem. 269, 29,343–29,346.Google Scholar
- Stefanelli, C., Stanic, I., Bonavita, F., Flamigni, F., Pignatti, C., Guarnieri, C., and Caldarera, C. M. (1998) Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 243, 821–826.PubMedCrossRefGoogle Scholar