Neurotoxicity Research

, 5:385 | Cite as

Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease

Article

Abstract

In vivo, post-mortem and biopsy data suggest that coupled deelines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.

Keywords

Alzheimer disease Cytochrome oxidase Positron emission tomography Brain Energy Metabolism Oxidative phosphorylation Mitochondria Activation Glucose Blood flow Synapse Neurofibrillary tangles Senile plaques mRNA 

References

  1. Akiyama H, S Barger, S Barnum, B Bradt, J Bauer, GM Cole, NR Cooper, P Eikelenboom, M Emmerling, BL Fiebich, CE Finch, S Frautschy, WS Griffin, H Hampel, M Hull, G Landreth, L Lue, R Mrak, IR Mackenzie, PL McGeer, MK O'Banion, J Pachter, G Pasinetti, C Plata-Salaman, J Rogers, R Rydel, Y Shen, W Streit, R Strohmeyer, I Tooyoma, FL Van Muiswinkel, R Weerhuis, D Walker, S Webster, B Wegrzyniak, G Wenk and T Wyss-Coray (2000) Inflammation and Alzheimer's disease.Neurobiol. Aging 21, 383–421.PubMedCrossRefGoogle Scholar
  2. Attardi G and G Schatz (1988) Biogenesis of mitochondria.Annu. Rev. Cell Biol. 4, 289–333.PubMedCrossRefGoogle Scholar
  3. Barger SW and AS Basile (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function.J. Neurochem. 76, 846–854.PubMedCrossRefGoogle Scholar
  4. Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases.Biochim. Biophys. Acta 1366, 211–223.PubMedCrossRefGoogle Scholar
  5. Bookheimer SY, MH Strojwas, MS Cohen, AM Saunders, MA Pericak-Vance, JC Mazziotta, and GW Small (2000) Patterns of brain activation in people at risk for Alzheimer's disease.N. Engl. J. Med. 343, 450–456.PubMedCrossRefGoogle Scholar
  6. Braak H and E Braak (1998) Evolution of neuronal changes in the course of Alzheimer's disease.J. Neural Transm. Suppl. 53, 127–140.PubMedGoogle Scholar
  7. Brodal A (1981)Neurological Anatomy in Relation to Clinical Medicine, 3rd Ed. (Oxford University Press, Oxford).Google Scholar
  8. Burggren AC, GW Small, FW Sabb and SY Bookheimer (2002) Specificity of brain activation patterns in people at genetic risk for Alzheimer disease.Am. J. Geriatr. Psychiatry 10, 44–51.PubMedGoogle Scholar
  9. Calingasan NY, K Uchida and GE Gibson (1999) Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer's disease.J. Neurochem. 72, 751–756.PubMedCrossRefGoogle Scholar
  10. Chandrasekaran K, J Stoll, DR Brady and SI Rapoport (1992) Localization of cytochrome oxidase (COX) activity and COX mRNA in the hippocampus and entorhinal cortex in the monkey brain: correlation with specific neuronal pathways.Brain Res. 579, 333–336.PubMedCrossRefGoogle Scholar
  11. Chandrasekaran K, J Stoll, SI Rapoport and DR Brady (1993) Localization of cytochrome oxidase (COX) activity and COX mRNA in the perirhinal and superior temporal sulci of the monkey brain.Brain Res. 606, 213–219.PubMedCrossRefGoogle Scholar
  12. Chandrasekaran K, T Giordano, DR Brady, J Stoll, LJ Martin and SI Rapoport (1994) Impairment of mitochondrial cytochrome oxidase gene expression in Alzheimer disease.Brain Res. Mol. Brain Res. 24 (S-1), 336–340.PubMedCrossRefGoogle Scholar
  13. Chandrasekaran K, K Hatanpää, DR Brady and SI Rapoport (1996) Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease.Exp. Neurol. 142, 80–88.PubMedCrossRefGoogle Scholar
  14. Chandrasekaran K, K Hatanpää, SI Rapoport and DR Brady (1997) Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex of Alzheimer disease.Brain Res. Mol. Brain Res. 44, 99–104.PubMedCrossRefGoogle Scholar
  15. Chandrasekaran K, K Hatanpää, DR Brady, J Stoll and SI Rapoport (1998) Downregulation of oxidative phosphorylation in Alzheimer disease: loss of cytochrome oxidase subunit mRNA in the hippocampus and entorhinal cortex.Brain Res. 796, 13–19.PubMedCrossRefGoogle Scholar
  16. Chandrasekaran K and SI Rapoport (unpublished observations).Google Scholar
  17. Chrzanowska-Lightowlers ZM, T Preiss and RN Lightowlers (1994) Inhibition of mitochondrial protein synthesis promotes increased stability of nuclear-encoded respiratory gene transcripts.J. Biol. Chem. 269, 27322–27328.PubMedGoogle Scholar
  18. Davies CA, DMA Mann, PQ Sumpter and PO Yates (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease.J. Neurol. Sci. 78, 151–164.PubMedCrossRefGoogle Scholar
  19. DeCarli CS, JR Atack, MJ Ball, JA Kaye, CL Grady, P Fewster, KD Pettigrew, SI Rapoport and MB Schapiro (1992) Post-mortem regional neurofibrillary tangle densities but not senile plaque densities are related to regional cerebral metabolic rates for glucose during life in Alzheimer's disease patients.Neurodegeneration 1, 113–121.Google Scholar
  20. DeCarli C, DG Murphy, JA Gillette, JV Haxby, D Teichberg, MB Schapiro and B Horwitz (1994) Lack of age-related differences in temporal lobe volume of very healthy adults.Am. J. Neuroradiol. 15, 689–696.PubMedGoogle Scholar
  21. DeKosky ST and SW Scheff (1990) Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity.Ann. Neurol. 27, 457–464.PubMedCrossRefGoogle Scholar
  22. Folstein MF, SE Folstein and PR McHugh (1975) Mini Mental State. A practical method for grading the cognitive state of patients for the clinician.J. Psychiatr. Res. 12, 189–198.PubMedCrossRefGoogle Scholar
  23. Fukuyama R, K Hatanpää, SI Rapoport and K Chandrasekaran (1996) Gene expression of ND4, a subunit of complex I of oxidative phosphorylation in mitochondria, is decreased in temporal cortex of brains of Alzheimer's disease patients.Brain Res. 713, 290–293.PubMedCrossRefGoogle Scholar
  24. Gaines G, C Rossi and G Attardi (1987) Markedly different ATP requirements for rRNA synthesis and mtDNA light strand transcription versus mRNA synthesis in isolated human mitochondria.J. Biol. Chem. 262, 1907–1915.PubMedGoogle Scholar
  25. Gelfand R and G Attardi (1981) Synthesis and turnover of mitochondrial ribonucleic acid in HeLa cells: the mature ribosomal and messenger ribonucleic acid species are metabolically unstable.Mol. Cell. Biol. 1, 497–511.PubMedGoogle Scholar
  26. Gong Y, L Chang, KL Viola, PN Lacor, MP Lambert, CE Finch, GA Krafft and WL Klein (2003) Alzheimer's disease-affected brain: presence of oligomeric Abeta ligands (ADDLs) suggests a molecular basis for reversible memory loss.Proc. Natl. Acad. Sci. USA 100, 10417–10422.PubMedCrossRefGoogle Scholar
  27. Grady CL (2002) Age-related differences in face processing: a meta-analysis of three functional neuroimaging experiments.Can. J. Exp. Psychol. 56, 208–220.PubMedGoogle Scholar
  28. Grady CL, B Sonies, J Haxby, J Luxenberg, R Friedland and S Rapoport (1988) Cerebral metabolic asymmetries predict decline in language performance in dementia of the Alzheimer type (DAT).J. Clin. Exp. Neuropsychol. 10, 39.Google Scholar
  29. Grady CL, JV Haxby, B Horwitz, J Gillette, JA Salerno, A Gonzalez-Aviles, RE Carson, P Herscovitch, MB Schapiro and SI Rapoport (1993) Activation of cerebral blood flow during a visuoperceptual task in patients with Alzheimer-type dementia.Neurobiol. Aging 14, 35–44.PubMedCrossRefGoogle Scholar
  30. Greenamyre JT, WF Maragos, RL Albin, JB Penney and AB Young (1988) Glutamate transmission and toxicity in Alzheimer's disease.Prog. Neuropsychopharmacol. Biol. Psychiatry 12, 421–430.PubMedCrossRefGoogle Scholar
  31. Greene JG and JT Greenamyre (1996) Bioenergetics and glutamate excitotoxicity.Prog. Neurobiol. 48, 613–634.PubMedCrossRefGoogle Scholar
  32. Hake AM and MR Farlow (2001) New concepts in the drug therapy of Alzheimer's disease.Expert Opin. Pharmacother. 2, 1975–1983.PubMedCrossRefGoogle Scholar
  33. Hatanpää K, DR Brady, J Stoll, SI Rapoport and K Chandrasekaran (1996) Neuronal activity and early neurofibrillary tangles in Alzheimer's disease.Ann. Neurol. 40, 411–420.PubMedCrossRefGoogle Scholar
  34. Hatanpää K, K Chandrasekaran, D Brady and SI Rapoport (1998) No association between Alzheimer plaques and decreased levels of cytochrome oxidase subunit mRNA, a marker of neuronal energy metabolism.Brain Res. Mol. Brain Res. 59, 13–21.PubMedCrossRefGoogle Scholar
  35. Hatanpää K, KR Isaacs, T Shirao, DR Brady and SI Rapoport (1999) Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease.J. Neuropathol. Exp. Neurol. 58, 637–643.PubMedCrossRefGoogle Scholar
  36. Haxby JV, R Duara, CL Grady, NR Cutler and SI Rapoport (1985) Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer's disease.J. Cereb. Blood Flow Metab. 5, 193–200.PubMedGoogle Scholar
  37. Hevner RF and MTT Wong-Riley (1991) Neuronal expression of nuclear and mitochondrial genes for cytochrome oxidase (CO) subunits analyzed byin situ hybridization: comparison with CO activity and protein.J. Neurosci. 11, 1942–1958.PubMedGoogle Scholar
  38. Hevner RF and MTT Wong-Riley (1993) Mitochondrial and nuclear gene expression for cytochrome oxidase subunits are disproportionately regulated by functional activity in neurons.J. Neurosci. 13, 1805–1819.PubMedGoogle Scholar
  39. Hevner RF, RS Duff and MT Wong-Riley (1992) Coordination of ATP production and consumption in brain: Parallel regulation of cytochrome oxidase and Na+, K+-ATPase.Neurosci. Lett. 138, 188–192.PubMedCrossRefGoogle Scholar
  40. Ibanez V, P Pietrini, GE Alexander, ML Furey, D Teichberg, JC Rajapakse, SI Rapoport, MB Schapiro and B Horwitz (1998) Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease.Neurology 50, 1585–1593.PubMedGoogle Scholar
  41. Iqbal K, C Alonso Adel, E El-Akkad, CX Gong, N Haque, S Khatoon, I Tsujio and I Grundke-Iqbal (2002) Pharmacological targets to inhibit Alzheimer neurofibrillary degeneration.J. Neural Transm. Suppl. 62, 309–319.PubMedGoogle Scholar
  42. Irizarry MC, F Soriano, M McNamara, KJ Page, D Schenk, D Games and BT Hyman (1997) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse.J. Neurosci. 17, 7053–7059.PubMedGoogle Scholar
  43. Katzman R (1976) The prevalence and malignancy of Alzheimer disease: a major killer.Arch. Neurol. 33, 217–218.PubMedGoogle Scholar
  44. Kennedy AM, RSJ Frackowiak, SK Newman, PM Bloomfield, J Seaward, P Roques, G Lewington, VJ Cunningham and MN Rossor (1995) Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease.Neurosci. Lett. 186, 17–20.PubMedCrossRefGoogle Scholar
  45. Kumar A, MB Schapiro, C Grady, JV Haxby, E Wagner, JA Salerno, RP Friedland and SI Rapoport (1991) High-resolution PET studies in Alzheimer's disease.Neuropsychopharmacology 4, 35–46.PubMedGoogle Scholar
  46. Lehninger AL, DL Nelson and MM Cox (1993)Principles of Biochemistry, 2nd Ed., Chapter 15, pp. 446–448; Chapter 20, pp. 669–683 (Worth Press: New York).Google Scholar
  47. Lewis DA, MJ Campbell, RD Terry and JH Morrison (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices.J. Neurosci. 7, 1799–1808.PubMedGoogle Scholar
  48. Liu LI, SI Rapoport and K Chandrasekaran (1999) Regulation of mitochondrial gene expression in differentiated PC12 cells.Ann. NY Acad. Sci. 893, 341–344.PubMedCrossRefGoogle Scholar
  49. Mann DMA, B Marcyniuk, PO Yates, D Neary and JS Snowden (1988) The progression of the pathological changes of Alzheimer's disease in frontal and temporal neocortex examined both at biopsy and at autopsy.Neuropathol. Appl. Neurobiol. 14, 177–195.PubMedCrossRefGoogle Scholar
  50. Masliah E and E Rockenstein (2000) Genetically altered transgenic models of Alzheimer's disease.J. Neurol. Transm. Suppl. 59, 175–183.Google Scholar
  51. Mattson MP, DS Gary, SL Chan, W Duan, SW Barger and AS Basile (2001) Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease.Biochem. Soc. Symp. 76, 151–162.Google Scholar
  52. Mecocci P, U MarGarvey and MF Beal (1994) Oxidative damage to mitochondria DNA is increased in Alzheimer disease.Ann. Neurol. 36, 747–751.PubMedCrossRefGoogle Scholar
  53. Mentis MJ, B Horwitz, CL Grady, GE Alexander, JW VanMeter, JM Maisog, P Pietrini, MB Schapiro and SI Rapoport (1996) Visual cortical dysfunction in Alzheimer's disease evaluated with a temporally graded “stress test” during PET.Am. J. Psychiatry 153, 32–40.PubMedGoogle Scholar
  54. Mentis MJ, GE Alexander, CL Grady, B Horwitz, J Krasuski, P Pietrini, T Strassburger, H Hampel, MB Schapiro and SI Rapoport (1997) Frequency variation of a pattern-flash visual stimulus during PET differentially activates brain from striate through frontal cortex.Neuroimage 5, 116–128.PubMedCrossRefGoogle Scholar
  55. Mentis MJ, GE Alexander, J Krasuski, P Pietrini, ML Furey, MB Schapiro and SI Rapoport (1988) Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation.Am. J. Psychiatry 155, 785–794.Google Scholar
  56. Mentis MJ, T Sunderland, J Lai, C Connolly, J Krasuski, B Levine, J Friz, S Sobti, M Schapiro and SI Rapoport (2001) Muscarinic versus nicotinic modulation of a visual task. A PET study using drug probes.Neuropsychopharmacology 25, 555–564.PubMedCrossRefGoogle Scholar
  57. Micol V, P Fernandez-Silva and G Attardi (1997) Functional analysis ofin vivo andin organello footprinting of HeLa cell mitochondrial DNA in relationship to ATP and ethidium bromide effects on transcription.J. Biol. Chem. 272, 18896–18904.PubMedCrossRefGoogle Scholar
  58. Montoya J, T Christianson, D Levens, M Rabinowitz and G Attardi (1982) Identification of initiation sites for heavy-strand and light-strand transcription in human mitochondrial DNA.Proc. Natl. Acad. Sci. USA 79, 7195–7199.PubMedCrossRefGoogle Scholar
  59. Mrak RE and WS Griffin (2001) Interleukin-1, neuroinflammation, and Alzheimer's disease.Neurobiol. Aging 22, 903–908.PubMedCrossRefGoogle Scholar
  60. Nagy Z, MM Esiri, M LeGris and PM Matthews (1999) Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology.Acta Neuropathol. (Berl.) 97, 346–354.CrossRefGoogle Scholar
  61. Parker Jr WD, J Parks, CM Filley and BK Kleinschmidt-DeMasters (1994) Electron transport chain defects in Alzheimer's disease brain.Neurology 44, 1090–1096.PubMedGoogle Scholar
  62. Pellmar TC, DA Schauer and GH Zeman (1990) Time-and dosedependent changes in neuronal activity produced by X radiation in brain slices.Radiation Res. 122, 209–214.PubMedCrossRefGoogle Scholar
  63. Peterson E (2003)Mild Cognitive Impairment: Aging to Alzheimer's Disease (Oxford University Press: New York), p. 269.Google Scholar
  64. Pietrini P, GE Alexander, ML Furey, A Dani, MJ Mentis, B Horwitz, M Guazzelli, MB Shapiro and SI Rapoport (2000) Cerebral metabolic response to passive audiovisual stimulation in patients with Alzheimer's disease and healthy volunteers assessed by PET.J. Nucl. Med. 41, 575–583.PubMedGoogle Scholar
  65. Purdon AD and SI Rapoport (1998) Energy requirements for two aspects of phospholipid metabolism in mammalian brain.Biochem. J. 335, 313–318.PubMedGoogle Scholar
  66. Rapoport SI (1990) Integrated phylogeny of the primate brain, with special reference to humans and their diseases.Brain Res. Rev. 15, 267–294.PubMedCrossRefGoogle Scholar
  67. Rapoport SI (1991) Positron emission tomography in Alzheimer's disease in relation to disease pathogenesis: a critical review.Cerebrovasc. Brain Metab. Rev. 3, 297–335.PubMedGoogle Scholar
  68. Rapoport SI (1995) Anatomic and functional brain imaging in Alzheimer's disease, In:Psychopharmacology: the Fourth Generation of Progress, Bloom FE and DJ Kupfer, Eds. (Raven: New York), pp. 1401–1415.Google Scholar
  69. Rapoport SI (1997) Deux stades, réversible et irréversible, de l'insuffisance fonctionnelle dans le cerveau Alzheimerien, In:De la Neurophysiologie à la Maladie D'Alzheimer: Symposium en Hommage à Yvon Lamour, Y. Christien, Eds. (Solal: Marseille), pp. 165–172.Google Scholar
  70. Rapoport SI and CL Grady (1993) Parametricin vivo brain imaging during activation to examine pathological mechanisms of functional failure in Alzheimer disease.Int. J. Neurosci. 70, 39–56.PubMedCrossRefGoogle Scholar
  71. Rapoport SI, K Hatanpää, DR Brady and K Chandrasekaran (1996) Brain energy metabolism, cognitive function and down-regulated oxidative phosphorylation in Alzheimer disease.Neurodegeneration 5, 473–476.PubMedCrossRefGoogle Scholar
  72. Reiman EM, RJ Caselli, LS Yun, K Chen, D Bandy, S Minoshima, SN Thibodeau and D Osbome (1996) Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E.N. Engl. J. Med. 334, 752–758.PubMedCrossRefGoogle Scholar
  73. Reivich M (1974) Blood flow metabolism couple in brain.Res. Publ. Assoc. Res. Nerv. Ment. Dis. 53, 125–140.PubMedGoogle Scholar
  74. Rojas-Fernandez CH, M Chen and HL Fernandez (2002) Implications of amyloid precursor protein and subsequent beta-amyloid production to the pharmacotherapy of Alzheimer's disease.Pharmacotherapy 22, 1547–1563.PubMedCrossRefGoogle Scholar
  75. Roy CS and CS Sherrington (1890) On the regulation of the blood supply of the brain.J. Physiol. (Lond.) 11, 85–105.Google Scholar
  76. Rutten BP, O Wirths, WD Van de Berg, SF Lichtenthaler, J Vehoff, HW Steinbusch, H Korr, K Beyreuther, G Multhaup, TA Bayer and C Schmitz (2003) No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment.Neurobiol. Dis. 12, 110–120.PubMedCrossRefGoogle Scholar
  77. Sato M, T Kawarabayashi, M Shoji, T Kobayashi, N Tada, E Matsubara and S Hirai (1997) Neurodegeneration and gliosis in transgenic mice overexpressing a carboxy-terminal fragment of Alzheimer amyloid-beta protein precursor.Dement. Geriatr. Cogn. Disord. 8, 296–307.PubMedCrossRefGoogle Scholar
  78. Scheff SW, ST DeKosky and DA Price (1990) Quantitative assessment of cortical synaptic density in Alzheimer's disease.Neurobiol. Aging 11, 29–37.PubMedCrossRefGoogle Scholar
  79. Scheff SW, DL Sparks and DA Price (1996) Quantitative assessment of synaptic density in the outer molecular layer of the hippocampal dentate gyrus in Alzheimer's disease.Dementia 7, 226–232.PubMedCrossRefGoogle Scholar
  80. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure.Science 298, 789–791.PubMedCrossRefGoogle Scholar
  81. Sheetz MP, ER Steuer and TA Schroer (1989) The mechanism and regulation of fast axonal transport.Trends Neurosci. 12, 474–478.PubMedCrossRefGoogle Scholar
  82. Sims NR, JM Finegan, JP Blass, DM Bowen and D Neary (1987) Mitochondrial function in brain tissue in primary degenerative dementia.Brain Res. 436, 30–38.PubMedCrossRefGoogle Scholar
  83. Small GW, JC Mazziotta, MT Collins, LR Baxter, ME Phelps, MA Mandelkern, A Kaplan, A La Rue, CF Adamson, L Chang, BH Guze, EH Corder, AM Saunders, JL Haines, MA Pericak-Vance and AD Roses (1995) Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease.JAMA 273, 942–947.PubMedCrossRefGoogle Scholar
  84. Sokoloff L (1999) Energetics of functional activation in neural tissues.Neurochem. Res. 24, 321–329.PubMedCrossRefGoogle Scholar
  85. Sorensen L, M Ekstrand, JP Silva, E Lindqvist, B Xu, P Rustin, L Olson and NG Larsson (2001) Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice.J. Neurosci. 21, 8082–8090.PubMedGoogle Scholar
  86. Talairach J and P Tournoux (1988) Co-planar stereotaxic atlas of the human brain (Thieme Medical Publishers, Inc.: New York).Google Scholar
  87. Tamataini M, K Chandrasekaran and CR Filburn (1987) unpublished observations.Google Scholar
  88. Terry RD, E Masliah, DP Salmon, N Butters, R DeTeresa, R Hill, LA Hansen and R Katzman (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 30, 572–580.PubMedCrossRefGoogle Scholar
  89. VanMeter JW, JM Maisog, TA Zeffiro, M Hallett, P Herscovitch and SI Rapoport (1995) Parametric analysis of functional neuroimages: application to a variable-rate motor task.Neuroimage 2, 272–383.CrossRefGoogle Scholar
  90. Wallace DC (1999) Mitochondrial diseases in man and mouse.Science 283, 1482–1488.PubMedCrossRefGoogle Scholar
  91. Wang SS, A Becerra-Arteaga and TA Good (2002) Development of a novel diffusion-based method to estimate the size of the aggregated Abeta species responsible for neurotoxicity.Biotechnol. Bioeng. 80, 50–59.PubMedCrossRefGoogle Scholar
  92. Wong-Riley MTT (1989) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity.Trends Neurosci. 12, 94–101.PubMedCrossRefGoogle Scholar
  93. Yaffe MP (1999) The machinery of mitochondrial inheritance and behavior.Science 283, 1493–1497.PubMedCrossRefGoogle Scholar
  94. Yao PJ, M Zhu, EI Pyun, AI Brooks, S Therianos, VE Meyers and PD Coleman (2003) Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease.Neurobiol. Dis. 12, 97–109.PubMedCrossRefGoogle Scholar
  95. Zhang C and MT Wong-Riley (2000) Synthesis and degradation of cytochrome oxidase subunit mRNAs in neurons: differential bigenomic regulation by neuronal activity.J. Neurosci. Res. 60, 338–344.PubMedCrossRefGoogle Scholar

Copyright information

© FP Graham Publishing Co 2003

Authors and Affiliations

  1. 1.Brain Physiology and Metabolism SectionsNational Institutes of HealthBethesdaUSA

Personalised recommendations