AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels During Synaptic Activation

Overview

Journal iScience

Publisher Cell Press

Date 2018 Oct 28

PMID 30368077

Citations 41

Authors

Claudia Marinangeli

Sebastien Didier

Tariq Ahmed

Raphaelle Caillerez

Manon Domise

Charlotte Laloux

Severine Begard

Sebastien Carrier

Morvane Colin

Philippe Marchetti

Bart Ghesquiere

Detlef Balschun

Luc Buee

Jerome Kluza

Valerie Vingtdeux

Affiliations

Soon will be listed here.

Abstract

Although the brain accounts for only 2% of the total body mass, it consumes the most energy. Neuronal metabolism is tightly controlled, but it remains poorly understood how neurons meet their energy demands to sustain synaptic transmission. Here we provide evidence that AMP-activated protein kinase (AMPK) is pivotal to sustain neuronal energy levels upon synaptic activation by adapting the rate of glycolysis and mitochondrial respiration. Furthermore, this metabolic plasticity is required for the expression of immediate-early genes, synaptic plasticity, and memory formation. Important in this context, in neurodegenerative disorders such as Alzheimer disease, dysregulation of AMPK impairs the metabolic response to synaptic activation and processes that are central to neuronal plasticity. Altogether, our data provide proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolic plasticity induced in response to synaptic activation and that its deregulation might lead to cognitive impairments.

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References

Hoey S, Williams R, Perkinton M . Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci. 2009; 29(14):4442-60. PMC: 6665739. DOI: 10.1523/JNEUROSCI.6017-08.2009. View

Dash P, Orsi S, Moore A . Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-Mammalian target of rapamycin pathway. J Neurosci. 2006; 26(31):8048-56. PMC: 6673778. DOI: 10.1523/JNEUROSCI.0671-06.2006. View

Bas-Orth C, Tan Y, Lau D, Bading H . Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect. J Biol Chem. 2017; 292(13):5183-5194. PMC: 5392666. DOI: 10.1074/jbc.M116.761106. View

Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F . The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron. 2013; 78(1):94-108. PMC: 3784324. DOI: 10.1016/j.neuron.2013.02.003. View

Boumezbeur F, Mason G, de Graaf R, Behar K, Cline G, Shulman G . Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 2009; 30(1):211-21. PMC: 2949111. DOI: 10.1038/jcbfm.2009.197. View

Suzuki A, Stern S, Bozdagi O, Huntley G, Walker R, Magistretti P . Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011; 144(5):810-23. PMC: 3073831. DOI: 10.1016/j.cell.2011.02.018. View

Caminiti S, Ballarini T, Sala A, Cerami C, Presotto L, Santangelo R . FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort. Neuroimage Clin. 2018; 18:167-177. PMC: 5790816. DOI: 10.1016/j.nicl.2018.01.019. View

McCrimmon R, Ryan C, Frier B . Diabetes and cognitive dysfunction. Lancet. 2012; 379(9833):2291-9. DOI: 10.1016/S0140-6736(12)60360-2. View

Jiang P, Gan M, Ebrahim A, Castanedes-Casey M, Dickson D, Yen S . Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of α-synuclein oligomers and decrease of neurites. Neurobiol Aging. 2012; 34(5):1504-15. PMC: 3570625. DOI: 10.1016/j.neurobiolaging.2012.11.001. View

10.

Lin M, Beal M . Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006; 443(7113):787-95. DOI: 10.1038/nature05292. View

11.

Divakaruni A, Wallace M, Buren C, Martyniuk K, Andreyev A, Li E . Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. J Cell Biol. 2017; 216(4):1091-1105. PMC: 5379957. DOI: 10.1083/jcb.201612067. View

12.

Xiao B, Heath R, Saiu P, Leiper F, Leone P, Jing C . Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature. 2007; 449(7161):496-500. DOI: 10.1038/nature06161. View

13.

Mosconi L . Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005; 32(4):486-510. DOI: 10.1007/s00259-005-1762-7. View

14.

Hwang J, Jiang L, Hamza M, Rangel E, Dai F, Belfort-DeAguiar R . Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM. JCI Insight. 2017; 2(20). PMC: 5846903. DOI: 10.1172/jci.insight.95913. View

15.

Weisova P, Concannon C, Devocelle M, Prehn J, Ward M . Regulation of glucose transporter 3 surface expression by the AMP-activated protein kinase mediates tolerance to glutamate excitation in neurons. J Neurosci. 2009; 29(9):2997-3008. PMC: 6666202. DOI: 10.1523/JNEUROSCI.0354-09.2009. View

16.

Whitlock J, Heynen A, Shuler M, Bear M . Learning induces long-term potentiation in the hippocampus. Science. 2006; 313(5790):1093-7. DOI: 10.1126/science.1128134. View

17.

Ferreira I, Resende R, Ferreiro E, Rego A, Pereira C . Multiple defects in energy metabolism in Alzheimer's disease. Curr Drug Targets. 2010; 11(10):1193-206. DOI: 10.2174/1389450111007011193. View

18.

Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A . A cannabinoid link between mitochondria and memory. Nature. 2016; 539(7630):555-559. DOI: 10.1038/nature20127. View

19.

Hawley S, Boudeau J, Reid J, Mustard K, Udd L, Makela T . Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003; 2(4):28. PMC: 333410. DOI: 10.1186/1475-4924-2-28. View

20.

Marinangeli C, Kluza J, Marchetti P, Buee L, Vingtdeux V . Study of AMPK-Regulated Metabolic Fluxes in Neurons Using the Seahorse XFe Analyzer. Methods Mol Biol. 2018; 1732:289-305. DOI: 10.1007/978-1-4939-7598-3_19. View