About this Journal Submit a Manuscript Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2006 (2006), Article ID 35936, 11 pages
http://dx.doi.org/10.1155/JBB/2006/35936
Review Article

The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK Inactivation, APP-CK Complexes and Focal Creatine Deposits

1Institute of Cell Biology, ETH Zurich, Hönggerberg HPM, Zurich CH-8093, Switzerland
2INSERM E0221, Laboratory of Fundamental and Applied Bioenergetics, University Joseph Fourier, Grenoble, France
3Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
4Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2

Received 12 December 2005; Revised 28 February 2006; Accepted 28 February 2006

Copyright © 2006 Tanja S. Bürklen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A III Ames, “CNS energy metabolism as related to function,” Brain Research. Brain Research Reviews, vol. 34, no. 1-2, pp. 42–68, 2000. View at Publisher · View at Google Scholar
  2. V Saks, P Dzeja, U Schlattner, M Vendelin, A Terzic, and T Wallimann, “Cardiac system bioenergetics: metabolic basis of Frank-Starling law,” The Journal of Physiology, vol. 571, no. pt 2, pp. 253–273, 2006. View at Publisher · View at Google Scholar
  3. T Wallimann, D C Turner, and H M Eppenberger, “Localization of creatine kinase isoenzymes in myofibrils. I. Chicken skeletal muscle,” The Journal of Cell Biology, vol. 75, pp. 297–317, 1977. View at Publisher · View at Google Scholar
  4. P Korge and S K Byrd, “Functional coupling between sarcoplasmic reticulum-bound creatine kinase and Ca(2+)-ATPase,” European Journal of Biochemistry, vol. 213, pp. 973–980, 1993. View at Publisher · View at Google Scholar
  5. A M Rossi, H M Eppenberger, P Volpe, R Cotrufo, and T Wallimann, “Muscle-type MM creatine kinase is specifically bound to sarcoplasmic reticulum and can support Ca2+ uptake and regulate local ATP/ADP ratios,” The Journal of Biological Chemistry, vol. 265, pp. 5258–5266, 1990.
  6. T Wallimann, T Schlosser, and H M Eppenberger, “Function of M-line-bound creatine kinase as intramyofibrillar ATP regenerator at the receiving end of the phosphorylcreatine shuttle in muscle,” The Journal of Biological Chemistry, vol. 259, pp. 5238–5246, 1984.
  7. S M Krause and W E Jacobus, “Specific enhancement of the cardiac myofibrillar ATPase by bound creatine kinase,” The Journal of Biological Chemistry, vol. 267, pp. 2480–2486, 1992.
  8. R Ventura-Clapier, H Mekhfi, and G Vassort, “Role of creatine kinase in force development in chemically skinned rat cardiac muscle,” The Journal of General Physiology, vol. 89, pp. 815–837, 1987. View at Publisher · View at Google Scholar
  9. R Grosse, E Spitzer, V V Kupriyanov, V A Saks, and K R Repke, “Coordinate interplay between (Na+ + K+)-ATPase and creatine phosphokinase optimizes (Na+/K+)-antiport across the membrane of vesicles formed from the plasma membrane of cardiac muscle cell,” Biochimica et Biophysica Acta, vol. 603, pp. 142–156, 1980.
  10. R F Booth and J B Clark, “Studies on the mitochondrially bound form of rat brain creatine kinase,” The Biochemical Journal, vol. 170, pp. 145–151, 1978.
  11. U Schlattner, M Tokarska-Schlattner, and T Wallimann, “Mitochondrial creatine kinase in human health and disease,” Biochimica et Biophysica Acta, 2005.
  12. M Kottke, V Adams, T Wallimann, V K Nalam, and D Brdiczka, “Location and regulation of octameric mitochondrial creatine kinase in the contact sites,” Biochimica et Biophysica Acta, vol. 1061, pp. 215–225, 1991.
  13. M Kottke, V Adam, I Riesinger, et al., “Mitochondrial boundary membrane contact sites in brain: points of hexokinase and creatine kinase location, and control of Ca2+ transport,” Biochimica et Biophysica Acta, vol. 935, pp. 87–102, 1988.
  14. W Biermans, A Bakker, and W Jacob, “Contact site between inner and outer mitochondrial membrane: a dynamic microcompartment for creatine kinase activity,” Biochimica et Biophysica Acta, vol. 1018, pp. 225–228, 1990.
  15. D Brdiczka, “Function of the outer mitochondrial compartment in regulation of energy metabolism,” Biochimica et Biophysica Acta, vol. 1187, pp. 264–269, 1994.
  16. W E Jacobus, “Respiratory control and the integration of heart high-energy phosphate metabolism by mitochondrial creatine kinase,” Annual Review of Physiology, vol. 47, pp. 707–725, 1985. View at Publisher · View at Google Scholar
  17. H M Eppenberger, D M Dawson, and N O Kaplan, “The comparative enzymology of creatine kinases. I. Isolation and characterization from chicken and rabbit tissues,” The Journal of Biological Chemistry, vol. 242, pp. 204–209, 1967.
  18. W Hemmer, E Zanolla, E M Furter-Graves, H M Eppenberger, and T Wallimann, “Creatine kinase isoenzymes in chicken cerebellum: specific localization of brain-type creatine kinase in Bergmann glial cells and muscle-type creatine kinase in Purkinje neurons,” The European Journal of Neuroscience, vol. 6, pp. 538–549, 1994. View at Publisher · View at Google Scholar
  19. M H Lerner and A J Friedhoff, “Characterization of a brain particulate bound form of creatine kinase,” Life Sciences, vol. 26, no. 23, pp. 1969–1976, 1980. View at Publisher · View at Google Scholar
  20. L Lim, C Hall, T Leung, L Mahadevan, and S Whatley, “Neurone-specific enolase and creatine phosphokinase are protein components of rat brain synaptic plasma membranes,” Journal of Neurochemistry, vol. 41, pp. 1177–1182, 1983. View at Publisher · View at Google Scholar
  21. S H Oliet, R Piet, and D A Poulain, “Control of glutamate clearance and synaptic efficacy by glial coverage of neurons,” Science, vol. 292, pp. 923–926, 2001. View at Publisher · View at Google Scholar
  22. E M Ullian, S K Sapperstein, K S Christopherson, and B A Barres, “Control of synapse number by glia,” Science, vol. 291, pp. 657–661, 2001. View at Publisher · View at Google Scholar
  23. W Shen, D Willis, Y Zhang, U Schlattner, T Wallimann, and G R Molloy, “Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebellum: evidence for transcriptional regulation,” The Biochemical Journal, vol. 367, pp. 369–380, 2002. View at Publisher · View at Google Scholar
  24. D Holtzman, M Tsuji, T Wallimann, and W Hemmer, “Functional maturation of creatine kinase in rat brain,” Developmental Neuroscience, vol. 15, pp. 261–270, 1993.
  25. A J Friedhoff and M H Lerner, “Creatine kinase isoenzyme associated with synaptosomal membrane and synaptic vesicles,” Life Sciences, vol. 20, no. 5, pp. 867–873, 1977. View at Publisher · View at Google Scholar
  26. C J Xu, W E Klunk, J N Kanfer, Q Xiong, G Miller, and J W Pettegrew, “Phosphocreatine dependent glutamate uptake by synaptic vesicles. A comparison with atpdependent glutamate uptake,” The Journal of Biological Chemistry, vol. 271, pp. 13435–13440, 1996. View at Publisher · View at Google Scholar
  27. F J Barrantes, A Braceras, H A Caldironi, et al., “Isolation and characterization of acetylcholine receptor membrane-associated (nonreceptor v2-protein) and soluble electrocyte creatine kinases,” The Journal of Biological Chemistry, vol. 260, pp. 3024–3034, 1985.
  28. Y Dunant, F Loctin, J Marsal, D Muller, A Parducz, and X Rabasseda, “Energy metabolism and quantal acetylcholine release: effects of botulinum toxin, 1-fluoro-2,4-dinitrobenzene, and diamide in the Torpedo electric organ,” Journal of Neurochemistry, vol. 50, pp. 431–439, 1988. View at Publisher · View at Google Scholar
  29. S T Brady and R J Lasek, “Nerve-specific enolase and creatine phosphokinase in axonal transport: soluble proteins and the axoplasmic matrix,” Cell, vol. 23, pp. 515–523, 1981. View at Publisher · View at Google Scholar
  30. M L Guerrero, J Beron, B Spindler, P Groscurth, T Wallimann, and F Verrey, “Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase,” The American Journal of Physiology, vol. 272, no. 2 pt 1, pp. C697–C706, 1997.
  31. M R Abraham, V A Selivanov, D M Hodgson, et al., “Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out,” The Journal of Biological Chemistry, vol. 277, pp. 24427–24434, 2002. View at Publisher · View at Google Scholar
  32. R M Crawford, H J Ranki, C H Botting, G R Budas, and A Jovanovic, “Creatine kinase is physically associated with the cardiac ATP-sensitive K+ channel in vivo,” The FASEB Journal, vol. 16, pp. 102–104, 2002.
  33. C R Jost, C E Van der Zee, H J In 't Zandt, et al., “Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility,” The European Journal of Neuroscience, vol. 15, pp. 1692–1706, 2002. View at Publisher · View at Google Scholar
  34. F Streijger, F Oerlemans, B A Ellenbroek, C R Jost, B Wieringa, and C E Van der Zee, “Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit,” Behavioural Brain Research, vol. 157, pp. 219–234, 2005. View at Publisher · View at Google Scholar
  35. D L Friedman and R Roberts, “Compartmentation of brain-type creatine kinase and ubiquitous mitochondrial creatine kinase in neurons: evidence for a creatine phosphate energy shuttle in adult rat brain,” The Journal of Comparative Neurology, vol. 343, pp. 500–511, 1994. View at Publisher · View at Google Scholar
  36. T Wallimann and W Hemmer, “Creatine kinase in non-muscle tissues and cells,” Molecular and Cellular Biochemistry, vol. 133-134, pp. 193–220, 1994. View at Publisher · View at Google Scholar
  37. P J Magistretti and L Pellerin, “Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging,” Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, vol. 354, pp. 1155–1163, 1999. View at Publisher · View at Google Scholar
  38. W F Mommaerts, K Seraydarian, M Suh, C J Kean, and A J Buller, “The conversion of some biochemical properties of mammalian skeletal muscles following cross-reinnervation,” Experimental Neurology, vol. 55, pp. 637–653, 1977. View at Publisher · View at Google Scholar
  39. T Wallimann, M Wyss, D Brdiczka, K Nicolay, and H M Eppenberger, “Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands : the “phosphocreatine circuit” for cellular energy homeostasis,” The Biochemical Journal, vol. 281, no. pt 1, pp. 21–40, 1992.
  40. B Focant and D C Watts, “Properties and mechanism of action of creatine kinase from ox smooth muscle,” The Biochemical Journal, vol. 135, pp. 265–276, 1973.
  41. S P Bessman and C L Carpenter, “The creatine-creatine phosphate energy shuttle,” Annual Review of Physiology, vol. 54, pp. 831–862, 1985.
  42. S P Bessman and P J Geiger, “Transport of energy in muscle: the phosphorylcreatine shuttle,” Science, vol. 211, pp. 448–452, 1981. View at Publisher · View at Google Scholar
  43. T Wallimann and H M Eppenberger, “Localization and function of M-line-bound creatine kinase. M-band model and creatine phosphate shuttle,” Cell and Muscle Motility, vol. 6, pp. 239–285, 1985.
  44. M R Iyengar, C E Fluellen, and C Iyengar, “Creatine kinase from the bovine myometrium: purification and characterization,” Journal of Muscle Research and Cell Motility, vol. 3, pp. 231–246, 1982. View at Publisher · View at Google Scholar
  45. R M Levin, P A Longhurst, and S S Levin, “Creatine kinase activity of urinary bladder and skeletal muscle from control and streptozotocin-diabetic rats,” Molecular and Cellular Biochemistry, vol. 97, pp. 153–159, 1990. View at Publisher · View at Google Scholar
  46. W I Norwood, J S Ingwall, C R Norwood, and T E Fossel, “Developmental changes of creatine kinase metabolism in rat brain,” The American Journal of Physiology, vol. 244, pp. C205–C210, 1983.
  47. W Hemmer and T Wallimann, “Functional aspects of creatine kinase in brain,” Developmental Neuroscience, vol. 15, pp. 249–260, 1993.
  48. S Ohtsuki, M Tachikawa, H Takanaga, et al., “The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 11, pp. 1327–1335, 2002.
  49. M Tachikawa, M Fukaya, T Terasaki, S Ohtsuki, and M Watanabe, “Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis,” The European Journal of Neuroscience, vol. 20, pp. 144–160, 2004. View at Publisher · View at Google Scholar
  50. O Braissant, T Gotoh, M Loup, M Mori, and C Bachmann, “L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study,” Brain Research. Molecular Brain Research, vol. 70, pp. 231–241, 1999. View at Publisher · View at Google Scholar
  51. O Braissant, H Henry, A M Villard, O Speer, T Wallimann, and C Bachmann, “Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1,” BMC Developmental Biology, vol. 5, p. 9, 2005. View at Publisher · View at Google Scholar
  52. O Braissant, H Henry, M Loup, B Eilers, and C Bachmann, “Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study,” Brain Research. Molecular Brain Research, vol. 86, pp. 193–201, 2001. View at Publisher · View at Google Scholar
  53. R Dringen, S Verleysdonk, B Hamprecht, W Willker, D Leibfritz, and A Brand, “Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione,” Journal of Neurochemistry, vol. 70, pp. 835–840, 1998.
  54. N Straumann, A Wind, T Leuenberger, and T Wallimann, “Effects of N-linked glycosylation on the creatine transporter,” The Biochemical Journal, 2005.
  55. T J deGrauw, K M Cecil, A W Byars, G S Salomons, W S Ball, and C Jakobs, “The clinical syndrome of creatine transporter deficiency,” Molecular and Cellular Biochemistry, vol. 244, pp. 45–48, 2003. View at Publisher · View at Google Scholar
  56. A Schulze, “Creatine Deficiency Syndromes,” Molecular and Cellular Biochemistry, vol. 244, pp. 143–150, 2003. View at Publisher · View at Google Scholar
  57. M F Beal, “Energetics in the pathogenesis of neurodegenerative diseases,” Trends in Neurosciences, vol. 23, pp. 298–304, 2000. View at Publisher · View at Google Scholar
  58. D R Green and J C Reed, “Mitochondria and Apoptosis,” Science, vol. 281, pp. 1309–1312, 1998. View at Publisher · View at Google Scholar
  59. E J Kasarskis, S Berryman, J G Vanderleest, A R Schneider, and C J McClain, “Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death,” The American Journal of Clinical Nutrition, vol. 63, no. 1, pp. 130–137, 1996.
  60. M T Carri, A Ferri, A Battistoni, et al., “Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells,” FEBS Letters, vol. 414, no. 2, pp. 365–368, 1997. View at Publisher · View at Google Scholar
  61. L Siklos, J Engelhardt, Y Harati, R G Smith, F Joo, and S H Appel, “Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis,” Annals of Neurology, vol. 39, pp. 203–216, 1996. View at Publisher · View at Google Scholar
  62. D Schubert, “Glucose metabolism and Alzheimer's disease,” Ageing Research Reviews, vol. 4, pp. 240–257, 2005. View at Publisher · View at Google Scholar
  63. W Meier-Ruge, P Iwangoff, and C Bertoni-Freddari, “What is primary and what secondary for amyloid deposition in Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 719, pp. 230–237, 1994.
  64. K Herholz, “PET studies in dementia,” Annals of Nuclear Medicine, vol. 17, pp. 79–89, 2003.
  65. R Castellani, K Hirai, G Aliev, et al., “Role of mitochondrial dysfunction in Alzheimer's disease,” Journal of Neuroscience Research, vol. 70, pp. 357–360, 2002. View at Publisher · View at Google Scholar
  66. D J Selkoe, “Translating cell biology into therapeutic advances in Alzheimer's disease,” Nature, vol. 399, pp. A23–A31, 1999. View at Publisher · View at Google Scholar
  67. D H Small and C A McLean, “Alzheimer's disease and the amyloid beta protein: what is the role of amyloid?” Journal of Neurochemistry, vol. 73, pp. 443–449, 1999. View at Publisher · View at Google Scholar
  68. S Hoyer, “Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications,” Advances in Experimental Medicine and Biology, vol. 541, pp. 135–152, 2004.
  69. W D Jr Parker, “Cytochrome oxidase deficiency in Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 640, pp. 59–64, 1991.
  70. S M de la Monte, T Luong, T R Neely, D Robinson, and J R Wands, “Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease,” Laboratory Investigation, vol. 80, pp. 1323–1335, 2000.
  71. I Maurer, S Zierz, and H J Moller, “A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients,” Neurobiology of Aging, vol. 21, no. 3, pp. 455–462, 2000. View at Publisher · View at Google Scholar
  72. J Valla, J D Berndt, and F Gonzalez-Lima, “Energy hypometabolism in posterior cingulate cortex of Alzheimer's patients: superficial laminar cytochrome oxidase associated with disease duration,” The Journal of Neuroscience , vol. 21, pp. 4923–4930, 2001.
  73. M Gallant, M Rak, A Szeghalmi, et al., “Elevated levels of creatine detected in APP transgenic mice and Alzeimer diseases brain tissue,” The Journal of Biological Chemistry, 2005.
  74. A Boveris and E Cadenas, “Mitochondrial production of hydrogen peroxide regulation by nitric oxide and the role of ubisemiquinone,” IUBMB Life, vol. 50, pp. 245–250, 2000. View at Publisher · View at Google Scholar
  75. M Y Aksenov, H M Tucker, P Nair, et al., “The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochromec oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer's disease,” Neurochemical Research, vol. 24, no. 6, pp. 767–774, 1999. View at Publisher · View at Google Scholar
  76. S M Cardoso, M T Proenca, S Santos, I Santana, and C R Oliveira, “Cytochrome c oxidase is decreased in Alzheimer's disease platelets,” Neurobiology of Aging, vol. 25, pp. 105–110, 2004. View at Publisher · View at Google Scholar
  77. J W Lustbader, M Cirilli, C Lin, et al., “ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease,” Science, vol. 304, pp. 448–452, 2004. View at Publisher · View at Google Scholar
  78. Z Li, K Okamoto, Y Hayashi, and M Sheng, “The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses,” Cell, vol. 119, pp. 873–887, 2004. View at Publisher · View at Google Scholar
  79. C Pereira, P Agostinho, P I Moreira, S M Cardoso, and C R Oliveira, “Alzheimer's disease associated neurotoxic mechanisms and neuroprotective strategies,” Current Drug Targets. CNS and Neurological Disorders, vol. 4, pp. 383–403, 2005. View at Publisher · View at Google Scholar
  80. W R Markesbery, “Oxidative stress hypothesis in Alzheimer's disease,” Free Radical Biology & Medicine, vol. 23, pp. 134–147, 1997.
  81. D A Butterfield and C M Lauderback, “Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress,” Free Radical Biology & Medicine, vol. 32, pp. 1050–1060, 2002.
  82. C D Smith, J M Carney, P E Starke-Reed, et al., “Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, pp. 10540–10543, 1991. View at Publisher · View at Google Scholar
  83. A Castegna, M Aksenov, V Thongboonkerd, et al., “Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71,” Journal of Neurochemistry, vol. 82, pp. 1524–1532, 2002. View at Publisher · View at Google Scholar
  84. S David, M Shoemaker, and B E Haley, “Abnormal properties of creatine kinase in Alzheimer's disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol-membrane partitioning,” Brain Research. Molecular Brain Research, vol. 54, pp. 276–287, 1998. View at Publisher · View at Google Scholar
  85. O Stachowiak, M Dolder, T Wallimann, and C Richter, “Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation,” The Journal of Biological Chemistry, vol. 273, pp. 16694–16699, 1998. View at Publisher · View at Google Scholar
  86. K Hensley, N Hall, R Subramaniam, et al., “Brain regional correspondence between Alzheimer's disease histopathology and biomarkers of protein oxidation,” Journal of Neurochemistry, vol. 65, pp. 2146–2156, 1995.
  87. M Aksenov, M Aksenova, D A Butterfield, and W R Markesbery, “Oxidative modification of creatine kinase BB in Alzheimer's disease brain,” Journal of Neurochemistry, vol. 74, pp. 2520–2527, 2000. View at Publisher · View at Google Scholar
  88. J W Pettegrew, K Panchalingam, W E Klunk, R J McClure, and L R Muenz, “Alterations of cerebral metabolism in probable Alzheimer's disease: a preliminary study,” Neurobiology of Aging, vol. 15, pp. 117–132, 1994. View at Publisher · View at Google Scholar
  89. X Li, T Burklen, X Yuan, et al., “Stabilization of ubiquitous mitochondrial creatine kinase preprotein by APP family proteins,” Molecular and Cellular Neurosciences, 2005.
  90. D Gabuzda, J Busciglio, L B Chen, P Matsudaira, and B A Yankner, “Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative,” The Journal of Biological Chemistry, vol. 269, pp. 13623–13628, 1994.
  91. D Kogel, R Schomburg, T Schurmann, et al., “The amyloid precursor protein protects PC12 cells against endoplasmic reticulum stress-induced apoptosis,” Journal of Neurochemistry, vol. 87, pp. 248–256, 2003. View at Publisher · View at Google Scholar
  92. Y Xie, Z Yao, H Chai, W M Wong, and W Wu, “Potential roles of Alzheimer precursor protein A4 and beta-amyloid in survival and function of aged spinal motor neurons after axonal injury,” Journal of Neuroscience Research, vol. 73, pp. 557–564, 2003. View at Publisher · View at Google Scholar
  93. M Citron, T Oltersdorf, C Haass, et al., “Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production,” Nature, vol. 360, pp. 672–674, 1992. View at Publisher · View at Google Scholar
  94. E E Clarke and M S Shearman, “Quantitation of amyloid-beta peptides in biological milieu using a novel homogeneous time-resolved fluorescence (HTRF) assay,” Journal of Neuroscience Methods, vol. 102, pp. 61–68, 2000. View at Publisher · View at Google Scholar
  95. A Eckert, B Steiner, C Marques, et al., “Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation,” Journal of Neuroscience Research, vol. 64, pp. 183–192, 2001. View at Publisher · View at Google Scholar
  96. R H Swerdlow and S M Khan, “A “mitochondrial cascade hypothesis” for sporadic Alzheimer's disease,” Medical Hypotheses, vol. 63, pp. 8–20, 2004. View at Publisher · View at Google Scholar
  97. A Eckert, U Keil, S Kressmann, et al., “Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress,” Pharmacopsychiatry, vol. 36, no. suppl 1, pp. S15–S23, 2003. View at Publisher · View at Google Scholar
  98. M G Bemben and H S Lamont, “Creatine supplementation and exercise performance: recent findings,” Sports Medicine, vol. 35, no. 2, pp. 107–125, 2005. View at Publisher · View at Google Scholar
  99. P Hespel, B Op't Eijnde, M Van Leemputte, et al., “Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans,” The Journal of Physiology, vol. 536, no. pt 2, pp. 625–633, 2001. View at Publisher · View at Google Scholar
  100. G J Brewer and T W Wallimann, “Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons,” Journal of Neurochemistry, vol. 74, no. 5, pp. 1968–1978, 2000. View at Publisher · View at Google Scholar
  101. P G Sullivan, J D Geiger, M P Mattson, and S W Scheff, “Dietary supplement creatine protects against traumatic brain injury,” Annals of Neurology, vol. 48, no. 5, pp. 723–729, 2000. View at Publisher · View at Google Scholar
  102. N Brustovetsky, T Brustovetsky, and J M Dubinsky, “On the mechanisms of neuroprotection by creatine and phosphocreatine,” Journal of Neurochemistry, vol. 76, no. 2, pp. 425–434, 2001. View at Publisher · View at Google Scholar
  103. V A Saks, I V Dzhaliashvili, and E A Konorev, “Molecular and cellular aspects of the cardioprotective mechanism of phosphocreatine,” Biokhimiia, vol. 57, no. 12, pp. 1763–1784, 1992.
  104. R H Andres, A D Ducray, A W Huber, et al., “Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue,” Journal of Neurochemistry, vol. 95, no. 1, pp. 33–45, 2005. View at Publisher · View at Google Scholar
  105. R H Andres, A D Ducray, A Perez-Bouza, et al., “Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system,” Cell Transplantation, vol. 14, no. 8, pp. 537–550, 2005.
  106. R H Andres, A W Huber, U Schlattner, et al., “Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue,” Neuroscience, vol. 133, no. 3, pp. 701–713, 2005. View at Publisher · View at Google Scholar
  107. A Ducray, S Kipfer, A W Huber, et al., “Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures,” Neuroscience Letters, vol. 395, no. 1, pp. 57–62, 2005. View at Publisher · View at Google Scholar
  108. B Wilken, J M Ramirez, I Probst, D W Richter, and F Hanefeld, “Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation,” Archives of Disease in Childhood. Fetal and Neonatal Edition, vol. 82, no. 3, pp. F224–F227, 2000. View at Publisher · View at Google Scholar
  109. K H Adcock, J Nedelcu, T Loenneker, E Martin, T Wallimann, and B P Wagner, “Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia,” Developmental Neuroscience, vol. 24, no. 5, pp. 382–388, 2002. View at Publisher · View at Google Scholar
  110. M Balestrino, M Lensman, M Parodi, et al., “Role of creatine and phosphocreatine in neuronal protection from anoxic and ischemic damage,” Amino Acids, vol. 23, no. 1–3, pp. 221–229, 2002. View at Publisher · View at Google Scholar
  111. A G Rabchevsky, P G Sullivan, I Fugaccia, and S W Scheff, “Creatine diet supplement for spinal cord injury: influences on functional recovery and tissue sparing in rats,” Journal of Neurotrauma, vol. 20, no. 7, pp. 659–669, 2003. View at Publisher · View at Google Scholar
  112. O N Hausmann, K Fouad, T Wallimann, and M E Schwab, “Protective effects of oral creatine supplementation on spinal cord injury in rats,” The Journal of Spinal Cord Medicine, vol. 40, no. 9, pp. 449–456, 2002. View at Publisher · View at Google Scholar
  113. P Klivenyi, Y N Calingasan, A Starkov, et al., “Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase,” Neurobiology of Disease, vol. 15, no. 3, pp. 610–617, 2004. View at Publisher · View at Google Scholar
  114. E Pena-Altamira, C Crochemore, M Virgili, and A Contestabile, “Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation,” Brain Research, vol. 1058, no. 1-2, pp. 183–188, 2005. View at Publisher · View at Google Scholar
  115. S Zhu, M Li, B E Figueroa, et al., “Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice,” The Journal of Neuroscience , vol. 24, no. 26, pp. 5909–5912, 2004. View at Publisher · View at Google Scholar
  116. J M Shefner, M E Cudkowicz, D Schoenfeld, et al., “A clinical trial of creatine in ALS,” Neurology, vol. 63, no. 9, pp. 1656–1661, 2004.
  117. G J Groeneveld, J H Veldink, I van der Tweel, et al., “A randomized sequential trial of creatine in amyotrophic lateral sclerosis,” Annals of Neurology, vol. 53, pp. 437–445, 2003. View at Publisher · View at Google Scholar
  118. A Bender, D P Auer, T Merl, et al., “Creatine supplementation lowers brain glutamate levels in Huntington's disease,” Journal of Neurology, vol. 252, no. 1, pp. 36–41, 2005. View at Publisher · View at Google Scholar
  119. S M Hersch, S Gevorkian, K Marder, et al., “Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG,” Neurology, vol. 66, no. 2, pp. 250–252, 2006. View at Publisher · View at Google Scholar
  120. M A Tarnopolsky, D K Simon, B D Roy, et al., “Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation,” Muscle & Nerve, vol. 29, no. 4, pp. 537–547, 2004.
  121. A M Stadhouders, P H Jap, H P Winkler, H M Eppenberger, and T Wallimann, “Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 5089–5093, 1994. View at Publisher · View at Google Scholar
  122. A C Ellis and J Rosenfeld, “The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders,” CNS Drugs, vol. 18, no. 14, pp. 967–980, 2004. View at Publisher · View at Google Scholar
  123. E M Snyder, Y Nong, C G Almeida, et al., “Regulation of NMDA receptor trafficking by amyloid-beta,” Nature Neuroscience, vol. 8, no. 8, pp. 1051–1058, 2005. View at Publisher · View at Google Scholar
  124. A Watanabe, N Kato, and T Kato, “Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation,” Neuroscience Research, vol. 42, no. 4, pp. 279–285, 2002. View at Publisher · View at Google Scholar
  125. C Rae, A L Digney, S R McEwan, and T C Bates, “Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo controlled, cross-over trial,” Proceedings. Biological Sciences, vol. 270, no. 1529, pp. 2147–2150, 2003. View at Publisher · View at Google Scholar
  126. L Kay, K Nicolay, B Wieringa, V Saks, and T Wallimann, “Direct evidence for the control of mitochondrial respiration by mitochondrial creatine kinase in oxidative muscle cells in situ,” The Journal of Biological Chemistry, vol. 275, no. 10, pp. 6937–6944, 2000. View at Publisher · View at Google Scholar
  127. E O'Gorman, G Beutner, M Dolder, A P Koretsky, D Brdiczka, and T Wallimann, “The role of creatine kinase in inhibition of mitochondrial permeability transition,” FEBS Letters, vol. 414, pp. 253–257, 1997.
  128. M Dolder, B Walzel, O Speer, U Schlattner, and T Wallimann, “Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation,” The Journal of Biological Chemistry, vol. 278, no. 20, pp. 17760–17766, 2003. View at Publisher · View at Google Scholar
  129. R B Ceddia and G Sweeney, “Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells,” The Journal of Physiology, vol. 555, no. pt 2, pp. 409–421, 2004. View at Publisher · View at Google Scholar
  130. D G Hardie and K Sakamoto, “AMPK: a key sensor of fuel and energy status in skeletal muscle,” Physiology (Bethesda), vol. 21, pp. 48–60, 2006.
  131. E F Burguera and B J Love, “Reduced transglutaminase-catalyzed protein aggregation is observed in the presence of creatine using sedimentation velocity,” Analytical Biochemistry, vol. 350, no. 1, pp. 113–119, 2005. View at Publisher · View at Google Scholar