Changes in brain energy metabolism and the early detection of Alzheimer’s disease

  • S. Hoyer
Part of the New Vistas in Drug Research book series (DRUG RESEARCH, volume 1)


Among the early and most prominent disturbances of dementia of Alzheimer type are glycolytic glucose breakdown and pyruvate oxidation, associated with an excessive protein catabolism in the brain. It is suggested that the abnormality in intracellular glucose homeostasis is caused by a deficiency at the insulin/insulin receptor level in the neuron, indicating resemblance to non-insulin dependent diabetes mellitus in non-nervous tissues, and a genetic influence as well. Therefore, non-nervous markers may help to detect AD: reduced activity of phosphofructokinase in skin fibroblasts; abnormal glucose tolerance test; abnormal morphology in nasal epithelium.


Alzheimer Type Nasal Epithelium Cerebral Metabolic Rate Cerebral Glucose Metabolism Brain Energy Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Bachelard HS (1971) Specific and kinetic properties of monosaccharide uptake into guinea pig cerebral cortex in vitro. J Neurochem 13: 213–222CrossRefGoogle Scholar
  2. Barkulis SS, Geiger A, Kawikata Y, Aguilar V (1960) A study of the incorporation of 14C-derived from glucose into free amino acids of the brain cortex. J Neurochem 5: 339–348PubMedCrossRefGoogle Scholar
  3. Bowen DM, White P, Spillane JA, Goodhardt MJ, Curzon G, Iwangoff P, Meier-Ruge W, Davison AN (1979) Accelerated ageing or selective neuronal loss as an important cause of dementia? Lancet is 11–14Google Scholar
  4. Browning M, Baudry M, Bennett WF, Lynch G (1981) Phosphorylation — mediated changes in pyruvate dehydrogenase activity influence pyruvate-supported calcium accumulation by brain mitochondria. J Neurochem 36: 1932–1940PubMedCrossRefGoogle Scholar
  5. Bucht G, Adolfsson R, Lithner F, Winblad B (1983) Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. Acta Med Scand 213: 387–392PubMedCrossRefGoogle Scholar
  6. Butcher SP, Sandberg M, Hagberg H, Hamberger A (1987) Cellular origins of endogeneous amino acids released into the extracellular fluid of the rat striatum during severe insulin-induced hypoglycemia. J Neurochem 48: 722–728PubMedCrossRefGoogle Scholar
  7. Butterworth RF, Merkel AD, Landreville F (1982) Regional amino acid distribution in relation to function in insulin hypoglycaemia. J Neurochem 38: 1483–1489PubMedCrossRefGoogle Scholar
  8. Chu DTW, Stumpo DJ, Blackshear PJ, Granner DL (1987) The inhibition of phosphoenolpyruvate carboxykinase (guanosine triphosphate) gene expression by insulin is not mediated by protein kinase C. Mol Endocrinol 1: 53–59PubMedCrossRefGoogle Scholar
  9. Cotman CW, Iversen LL (1987) Excitatory amino acids in the brain-focus on NMDA receptors. Trends Neurosci 10: 263–265CrossRefGoogle Scholar
  10. Cotman CW, Monaghan DT, Ottersen OP, Storm-Mathisen J (1987) Anatomical organization of excitatory amino acid receptors and their pathways. Trends Neurosci 10: 273–280CrossRefGoogle Scholar
  11. Davies SW, McBean GJ, Roberts PJ (1984) A glutamatergic innervation of the nucleus basalis/substantia innominata. Neurosci Lett 45: 105–110PubMedCrossRefGoogle Scholar
  12. DeLeon MJ, George AE, Marcus DL, Miller JD (1988) Positron emission tomography with the deoxyglucose technique and the diagnosis of Alzheimer’s disease. Neurobiol Aging 9: 90–92CrossRefGoogle Scholar
  13. Denton RM, McCormack JG, Thomas AP (1986) Hormonal regulation of intramitochondrial metabolism. Biol Chem Hoppe-Seyler 367 [Suppl]: 64Google Scholar
  14. Gammeltoft S, Kowalski A, Fehlmann M, van Obberghen E (1984) Insulin receptor in rat brain: insulin stimulates phosphorylation of its receptor 13-subunit. FEBS Lett 172: 87–90PubMedCrossRefGoogle Scholar
  15. Geiger A, Kawikata Y, Barkulis SS (1960) Major pathways of glucose utilization in the brain in brain-perfusion experiment in vivo and in situ. J Neurochem 5: 323–338PubMedCrossRefGoogle Scholar
  16. Gibbs EL, Lennox WG, Nims LF, Gibbs FA (1942) Arterial and cerebral venous blood. Arterial-venous differences in man. J Biol Chem 144: 325–332Google Scholar
  17. Gibson GE, Jope R, Blass JP (1975) Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces. Biochem J 148: 17–23PubMedGoogle Scholar
  18. Gottstein U, Bernsmeier A, Sedlmeyer I (1963) Der Kohlenhydratstoffwechsel des menschlichen Gehirns. I. Untersuchungen mit substratspezifischen enzymatischen Methoden bei normaler Hirndurchblutung. Klin Wschr 41: 943–948PubMedCrossRefGoogle Scholar
  19. Greenamyre JT, Young AB, Penny JB (1984) Quantitative autoradiographic distribution of L-(3H) glutamate-binding sites in rat central nervous system. J Neurosci 4: 2133–2144PubMedGoogle Scholar
  20. Hansford RG, Castro F (1985) Role of Ca2+ in pyruvate dehydrogenase interconversion in brain mitochondria and synaptosomes. Biochem J 227: 129–136PubMedGoogle Scholar
  21. Havrankova J, Schmelchel D, Roth J, Browstein M (1978) Identification of insulin in rat brain. Proc Natl Acad Sci USA 75: 5737–5741PubMedCrossRefGoogle Scholar
  22. Hertz MM, Paulson OB, Barry DI, Christiansen JS, Svendsen PA (1981) Insulin increases glucose transfer across the blood-brain barrier. J Clin Invest 67: 597–604PubMedCrossRefGoogle Scholar
  23. Hoyer S (1970) Der Aminosäurenstoffwechsel des normalen menschlichen Gehirns. Klin Wschr 48: 1239–1243PubMedCrossRefGoogle Scholar
  24. Hoyer S (1988) Glucose and related brain metabolism in dementia of Alz- heimer type and its morphological significance. Age 11: 158–166CrossRefGoogle Scholar
  25. Hoyer S, Krier C (1986) Ischemia and the aging brain. Studies on glucose and energy metabolism in rat cerebral cortex. Neurobiol Aging 7: 23–29PubMedCrossRefGoogle Scholar
  26. Hoyer S, Nitsch R (1989) Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J Neural Transm 75: 227–232PubMedCrossRefGoogle Scholar
  27. Hoyer S, Oesterreich K, Wagner O (1988) Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol 235: 143–148PubMedCrossRefGoogle Scholar
  28. Iwangoff P, Armbruster R, Enz A, Meier-Ruge W, Sandoz P (1980) Glycolytic enzymes from human autoptic brain cortex: normally aged and demented cases. In: Roberts PJ (ed) Biochemistry of dementia. Wiley, Chichester, pp 258–262Google Scholar
  29. Jahr CE, Stevens CF (1987) Glutamate activates multiple single channel conductances in hippocampal neurons. Nature 325: 522–525PubMedCrossRefGoogle Scholar
  30. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531PubMedCrossRefGoogle Scholar
  31. Kahn CR (1985) The molecular mechanism of insulin action. Ann Rev Med 36: 429–451PubMedCrossRefGoogle Scholar
  32. Kesslak JP, Cotman CW, Chui HC, van den Noort S, Fang H, Pfeffer R, Lynch G (1988) Olfactory tests as possible probes for detecting and monitoring Alzheimer’s disease. Neurobiol Aging 9: 399–403PubMedCrossRefGoogle Scholar
  33. Kyriakis JM, Hausman RE, Peterson SW (1987) Insulin stimulates choline acetyltransferase activity in cultured embryonic chicken retina neurons. Proc Natl Acad Sci USA 84: 7463–7467PubMedCrossRefGoogle Scholar
  34. Malthe-Sorensen D, Skrede K, Fonnum F (1980) Calcium dependent release of D-3H-aspartate from the dorsal septum after electrical stimulation of the fimbria in vitro. Neuroscience 5: 127–133CrossRefGoogle Scholar
  35. Monaghan DT, Holets VR, Toy DW, Cotman CW (1983) Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites. Nature 306: 176–179PubMedCrossRefGoogle Scholar
  36. Newsholme EA, Start C (1973) Regulation in metabolism. Wiley, Chichester, pp 100–104Google Scholar
  37. Nishizaki T, Yamauchi R, Okada Y (1988) Enhancement of the oxygen consumption in the hippocampal slices of the guinea pig induced by glutamate and its related substances. Neurosci Lett 85: 61–64PubMedCrossRefGoogle Scholar
  38. Norberg K, Siesjö BK (1976) Oxidative metabolism of the cerebral cortex of the rat in severe insulin-induced hypoglycaemia. J Neurochem 26: 345–352PubMedCrossRefGoogle Scholar
  39. Pearson RCA, Esiri MM, Hiorns RW, Wilcock GK, Powell TPS (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci 82: 4531–4534PubMedCrossRefGoogle Scholar
  40. Perry EK, Perry RH, Tomlinson BE, Blessed G, Gibson PH (1980) Coenzyme A acetylating enzymes in Alzheimer’s disease: possible cholinergic “compartment” of pyruvate dehydrogenase. Neurosci Lett 18: 105–110PubMedCrossRefGoogle Scholar
  41. Peterson C, Goldman JE (1986) Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA 83: 2758–2762PubMedCrossRefGoogle Scholar
  42. Peterson C, Gibson GE, Blass JP (1985) Altered calcium uptake in cultured skin fibroblasts from patients with Alzheimer’s disease. N Engl J Med 312: 1063–1065PubMedCrossRefGoogle Scholar
  43. Peterson C, Ratan RR, Shelanski ML, Goldman JE (1986) Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA 83: 7999–8001PubMedCrossRefGoogle Scholar
  44. Polinsky RJ, Noble H, DiChiro G, Nee LE, Feldman RG, Brown RT (1987) Dominantly inherited Alzheimer’s disease: cerebral glucose metabolism. J Neurol Neurosurg Psychiatry 50: 752–757PubMedCrossRefGoogle Scholar
  45. Procter AW, Palmer AM, Francis PT, Lowe SL, Neary D, Murphy E, Doshi R, Bowen DM (1988) Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s disease. J Neurochem 50: 790–802PubMedCrossRefGoogle Scholar
  46. Roth RA, Morgan DO, Beaudoin J, Sara V (1986) Purification and characterization of the human brain insulin receptor. J Biol Chem 261: 3753–3757PubMedGoogle Scholar
  47. Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic-ischaemic brain damage. Ann Neurol 19: 105–111PubMedCrossRefGoogle Scholar
  48. Sacks W (1957) Cerebral metabolism of isotopic glucose in normal human subjects. J Appl Physiol 10: 37–44PubMedGoogle Scholar
  49. Sacks W (1965) Cerebral metabolism of doubly labeled glucose in humans in vivo. J Appl Physiol 20: 117–130PubMedGoogle Scholar
  50. Siesjö BIB (1978) Brain energy metabolism. Wiley, Chichester, pp 1–55Google Scholar
  51. Sims NR, Blass JP (1986) Phosphofructokinase activity in fibroblasts from patients with Alzheimer’s disease and age-and sex-matched controls. Met Brain Dis 1: 83–90CrossRefGoogle Scholar
  52. Sims NR, Bowen DM, Smith CCT, Flack RHA, Davison AN, Snowdon JS, Neary D (1980) Glucose metabolism and acetylcholine synthesis in relation to neural activity in Alzheimer’s disease. Lancet is 333–336Google Scholar
  53. Sims NR, Bowen DM, Allen SJ, Smith CCT, Neary D, Thomas DJ, Davison AN (1983 a) Presynaptic cholinergic dysfunction in patients with dementia. J Neurochem 40: 503–509Google Scholar
  54. Sims NR, Bowen DM, Neary D, Davison AN (1983b) Metabolic processes in Alzheimer’s disease: adenine nucleotide content and production of 14CO2 from (U 74C) glucose in vitro in human neocortex. J Neurochem 41: 1329–1334PubMedCrossRefGoogle Scholar
  55. Sims NR, Finegan JM, Blass JP (1985 a) Altered glucose metabolism in fibroblasts from patients with Alzheimer’s disease. N Engl J Med 313: 638–639Google Scholar
  56. Sims NR, Finegan JM, Bowen DM, Blass JP (1985b) Mitochondrial function in Alzheimer’s disease measured in vitro using neocortical tissue homogenates. J Neurochem 44 [Suppl]: S 192Google Scholar
  57. Sims NR, Finegan JM, Blass JP, Bowen DM, Neary D (1987) Mitochondrial function in brain tissue in primary degenerative dementia. Brain Res 436: 30–38PubMedCrossRefGoogle Scholar
  58. Smith CCT, Bowen DM, Davison AN (1983) The evoked release of endogenous amino acids from tissue prisms of human neocortex. Brain Res 269: 103–109PubMedCrossRefGoogle Scholar
  59. Sorbi S, Blass JP (1983) Fibroblast phosphofructokinase in Alzheimer’s disease and Down’s syndrome. Banbury Report 15: Biological aspects of Alzheimer’s disease. Cold Spring Laboratory, pp 297–307Google Scholar
  60. Sorbi S, Bird ED, Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13: 72–78PubMedCrossRefGoogle Scholar
  61. Strange PG (1988) The structure and mechanisms of neurotransmitter receptors. Implications for the structure and function of the central nervous system. Biochem J 249: 309–318PubMedGoogle Scholar
  62. Sumpter PQ, Mann DMA, Davies CA, Yates PO, Snowdon JS, Neary D (1986) An ultrastructural analysis of the effects of accumulation of neurofibrillary tangles in pyramidal neurons of the cerebral cortex in Alzheimer’s disease. Neuropathol Appl Neurobiol 12: 305–319PubMedCrossRefGoogle Scholar
  63. Talamo BR, Rudel RA, Kosik KS, Lee VMY, Neff S, Adelman L, Kauer JS (1989) Pathological changes in olfactory neurons in patients with Alzheimer’s disease. Nature 337: 736–739PubMedCrossRefGoogle Scholar
  64. Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of Alzheimer type. Ann Neurol 10: 184–192PubMedCrossRefGoogle Scholar
  65. Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11: 205–242PubMedCrossRefGoogle Scholar
  66. Walaas I, Fonnum F (1980) Biochemical evidence for glutamate as a transmitter in hippocampal efferents to the basal forebrain and hypothalamus in the rat brain. Neuroscience 5: 1691–1698PubMedCrossRefGoogle Scholar
  67. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, Mendelsohn FAO (1987) Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121: 1562–1570PubMedCrossRefGoogle Scholar
  68. Wong KL, Tyce GM (1983) Glucose and amino acid metabolism in rat brain during sustained hypoglycemia. Neurochem Res 8: 401–415PubMedCrossRefGoogle Scholar
  69. Young WS (1986) Periventricular hypothalamic cells in the rat brain contain insulin mRNA. Neuropeptides 8: 93–97PubMedCrossRefGoogle Scholar
  70. Zanotto L, Heinemann U (1983) Aspartate and glutamate induced reactions in extracellular free calcium and sodium concentration in area CA1 of “in vitro” hippocampal slices of rats. Neurosci Lett 35: 79–84PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1990

Authors and Affiliations

  • S. Hoyer
    • 1
  1. 1.Department of Pathochemistry and General NeurochemistryUniversity of HeidelbergFederal Republic of Germany

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