Skip to main content
SpringerLink
Log in

Age-related changes in AMP-activated protein kinase after stroke

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Stroke-induced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abete P, Cacciatore F, Testa G, Della-Morte D, Galizia G, de Santis D, Calabrese C, Cioppa A, Ferrara N, Rengo F (2010) Ischemic preconditioning in the aging heart: from bench to bedside. Ageing Res Rev 9:153–162

    Article  PubMed  Google Scholar 

  • Alexis NE, Back T, Zhao W, Dietrich WD, Watson BD, Ginsberg MD (1996) Neurobehavioral consequences of induced spreading depression following photothrombotic middle cerebral artery occlusion. Brain Res 15:273–282

    Article  Google Scholar 

  • Anyanwu EC (2007) Neurochemical changes in the aging process: implications in medication in the elderly. Scientific World J 7:1603–1610

    Article  CAS  Google Scholar 

  • Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18:3004–3009

    Article  PubMed  CAS  Google Scholar 

  • Baquer NZ, Taha A, Kumar P, McLean P, Cowsik SM, Kale RK, Singh R, Sharma D (2009) A metabolic and functional overview of brain aging linked to neurological disorders. Biogerontology 10:377–413

    Article  PubMed  CAS  Google Scholar 

  • Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature 458:1056–1060

    Article  PubMed  CAS  Google Scholar 

  • Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17:45–58

    Article  PubMed  CAS  Google Scholar 

  • Fulco M, Sartorelli V (2008) Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7:3669–3679

    Article  PubMed  CAS  Google Scholar 

  • Gonzales RA, Brown LM, Jones TW, Trent RD, Westbrook SL, Leslie SW (1991) N-methyl-d-aspartate mediated responses decrease with age in Fischer 344 rat brain. Neurobiol Aging 12:219–225

    Article  PubMed  CAS  Google Scholar 

  • Grabowski M, Brundin P, Johansson BB (1993) Paw-reaching, sensorimotor, and rotational behavior after brain infarction in rats. Stroke 24:889–895

    Article  PubMed  CAS  Google Scholar 

  • Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785

    Article  PubMed  CAS  Google Scholar 

  • Hardie DG, Hawley SA (2001) AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays 23:1112–1119

    Article  PubMed  CAS  Google Scholar 

  • Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (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 271:27879–27887

    Article  PubMed  CAS  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  PubMed  CAS  Google Scholar 

  • Imai S (2007) Is Sirt1 a miracle bullet for longevity? Aging Cell 6:735–737

    Article  PubMed  CAS  Google Scholar 

  • Jung JE, Lee J, Ha J, Kim SS, Cho YH, Baik HH, Kang I (2004) 5-Aminoimidazole-4-carboxamide-ribonucleoside enhances oxidative stress-induced apoptosis through activation of nuclear factor-kappaB in mouse Neuro 2a neuroblastoma cells. Neurosci Lett 354:197–200

    Article  PubMed  CAS  Google Scholar 

  • Khaliulin I, Clarke SJ, Lin H, Parker J, Suleiman MS, Halestrap AP (2007) Temperature preconditioning of isolated rat hearts—a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore. J Physiol 581:1147–1161

    Article  PubMed  CAS  Google Scholar 

  • Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279:19970–19976

    Article  PubMed  CAS  Google Scholar 

  • Krieger DW, Yenari MA (2004) Therapeutic hypothermia for acute ischemic stroke: what do laboratory studies teach us? Stroke 35:1482–1489

    Article  PubMed  Google Scholar 

  • Kuramoto N, Wilkins ME, Fairfax BP, Revilla-Sanchez R, Terunuma M, Tamaki K, Iemata M, Warren N, Couve A, Calver A, Horvath Z, Freeman K, Carling D, Huang L, Gonzales C, Cooper E, Smart TG, Pangalos MN, Moss SJ (2007) Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 53:233–247

    Article  PubMed  CAS  Google Scholar 

  • Lazzaro MA, Prabhakaran S (2008) Induced hypothermia in acute ischemic stroke. Expert Opin Investig Drugs 17:1161–1174

    Article  PubMed  CAS  Google Scholar 

  • Li J, McCullough LD (2010) Effects of AMP-activated protein kinase in cerebral ischemia. J Cereb Blood Flow Metab 30:480–492

    Article  PubMed  CAS  Google Scholar 

  • Li J, Zeng Z, Viollet B, Ronnett GV, McCullough LD (2007) Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke 38:2992–2999

    Article  PubMed  CAS  Google Scholar 

  • Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD, McCullough LD (2004) Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol 187:94–104

    Article  PubMed  Google Scholar 

  • Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP (2009a) Nicotinamide prevents NAD + depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD + consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular Med 11:28–42

    Article  PubMed  CAS  Google Scholar 

  • Liu F, Yuan R, Benashski SE, McCullough LD (2009b) Changes in experimental stroke outcome across the life span. J Cereb Blood Flow Metab 29:792–802

    Article  PubMed  CAS  Google Scholar 

  • Ljubicic V, Hood DA (2009) Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle. Aging Cell 8:394–404

    Article  PubMed  CAS  Google Scholar 

  • Love S (2003) Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 27:267–282

    Article  PubMed  CAS  Google Scholar 

  • Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, Al-Sanani F, Lutsep H, Dobak J, Matsubara BS, Zivin J (2005) Intravascular cooling in the treatment of stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis 14:107–114

    Article  PubMed  Google Scholar 

  • McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005a) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25:502–512

    Article  PubMed  CAS  Google Scholar 

  • McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV (2005b) Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem 280:20493–20502

    Article  PubMed  CAS  Google Scholar 

  • Mulligan JD, Gonzalez AA, Kumar R, Davis AJ, Saupe KW (2005) Aging elevates basal adenosine monophosphate-activated protein kinase (AMPK) activity and eliminates hypoxic activation of AMPK in mouse liver. J Gerontol A Biol Sci Med Sci 60:21–27

    Article  PubMed  Google Scholar 

  • Nakatsu Y, Kotake Y, Hino A, Ohta S (2008) Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death. Toxicol Appl Pharmacol 230:358–363

    Article  PubMed  CAS  Google Scholar 

  • Nemoto S, Fergusson MM, Finkel T (2004) Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306:2105–2108

    Article  PubMed  CAS  Google Scholar 

  • Osiewacz HD (2002) Genes, mitochondria and aging in filamentous fungi. Ageing Res Rev 1:425–442

    Article  PubMed  CAS  Google Scholar 

  • Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142

    Article  PubMed  CAS  Google Scholar 

  • Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A, Gupta MP (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 285:3133–3144

    Article  PubMed  CAS  Google Scholar 

  • Qiang W, Weiqiang K, Qing Z, Pengju Z, Yi L (2007) Aging impairs insulin-stimulated glucose uptake in rat skeletal muscle via suppressing AMPKalpha. Exp Mol Med 39:535–543

    PubMed  CAS  Google Scholar 

  • Raval AP, Lin HW, Dave KR, Defazio RA, Della Morte D, Kim EJ, Perez-Pinzon MA (2008) Resveratrol and ischemic preconditioning in the brain. Curr Med Chem 15:1545–1551

    Article  PubMed  CAS  Google Scholar 

  • Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI (2007) Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 5:151–156

    Article  PubMed  CAS  Google Scholar 

  • Ronnett GV, Kim EK, Landree LE, Tu Y (2005) Fatty acid metabolism as a target for obesity treatment. Physiol Behav 85:25–35

    Article  PubMed  CAS  Google Scholar 

  • Ronnett GV, Ramamurthy S, Kleman AM, Landree LE, Aja S (2009) AMPK in the brain: its roles in energy balance and neuroprotection. J Neurochem 109(Suppl 1):17–23

    Article  PubMed  CAS  Google Scholar 

  • Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y (2008) Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:e25–e146

    Article  PubMed  Google Scholar 

  • Shapira S, Sapir M, Wengier A, Grauer E, Kadar T (2002) Aging has a complex effect on a rat model of ischemic stroke. Brain Res 925:148–158

    Article  PubMed  CAS  Google Scholar 

  • Suwa M, Nakano H, Radak Z, Kumagai S (2008) Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle. Metabolism 57:986–998

    Article  PubMed  CAS  Google Scholar 

  • Tissenbaum HA, Guarente L (2002) Model organisms as a guide to mammalian aging. Dev Cell 2:9–19

    Article  PubMed  CAS  Google Scholar 

  • Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–79

    Article  PubMed  CAS  Google Scholar 

  • Turdi S, Fan X, Li J, Zhao J, Huff AF, Du M, Ren J (2010) AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell 9:592–606

    Article  PubMed  CAS  Google Scholar 

  • Vingtdeux V, Davies P, Dickson DW, Marambaud P (2010) AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies. Acta Neuropathol. doi:10.1007/s00401-010-0759-x

  • Wang W, Yang X, Lopez de Silanes I, Carling D, Gorospe M (2003) Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function. J Biol Chem 278:27016–27023

    Article  PubMed  CAS  Google Scholar 

  • Weisova P, Davila D, Tuffy LP, Ward MW, Concannon CG, Prehn JH (2010) Role of AMP-activated protein kinase (AMPK) in cell survival and death responses in neurons. Antioxid Redox Signal. doi:10.1089/ars.2010.3544

  • Wenk GL, Walker LC, Price DL, Cork LC (1991) Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys. Neurobiol Aging 12:93–98

    Article  PubMed  CAS  Google Scholar 

  • Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689

    Article  PubMed  CAS  Google Scholar 

  • Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Institute of Neurological Diseases and Stroke (NINDS; NS050505 and NS055215 to LDM)

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA

    Fudong Liu, Sharon E. Benashski, Rebecca Persky, Yan Xu, Jun Li & Louise D. McCullough

  2. Department of Neurology, University of Connecticut Health Center and the Stroke Center at Hartford Hospital, 263 Farmington Ave, Farmington, CT, 06030, USA

    Louise D. McCullough

Authors
  1. Fudong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon E. Benashski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecca Persky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Louise D. McCullough
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Louise D. McCullough.

About this article

Cite this article

Liu, F., Benashski, S.E., Persky, R. et al. Age-related changes in AMP-activated protein kinase after stroke. AGE 34, 157–168 (2012). https://doi.org/10.1007/s11357-011-9214-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-011-9214-8

Keywords

Search

Navigation