Download PDF
Pharmacopsychiatry 2003; 36: 62-67
DOI: 10.1055/s-2003-40452
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Memory Function and Brain Glucose Metabolism

S. Hoyer1
  • 1Dept. of Pathochemistry and General Neurochemistry, Institute of Pathology of the University, Heidelberg, Germany
Further Information

Publication History

Publication Date:
07 July 2003 (online)

Also available at
    Permissions and Reprints

Memory formation and memory retrieval are subject to complex cellular and molecular processes. Increasing evidence exists that neuronal glucose metabolism and its control by the insulin signal transduction cascade are the main players in such processes. Acetylcholine synthesis depends on the availability of acetyl CoA, provided from glucose breakdown, and insulin, which controls the activity of acetylcholine transferase. ATP is necessary for both synaptic activity and plasticity. This is also true for APPs, the secreted derivative of APP. Trafficking of the latter protein is controlled by insulin and insulin receptor function also acting on activity-regulated cytoskeleton-associated gene expression, which induces biochemical stimuli involved in synaptic activity and plasticity. Any damage in neuronal glucose metabolism and its control may, therefore, cause disturbances in memory function - as is found for example in sporadic Alzheimer’s disease. Mimicking these metabolic and behavioral abnormalities in experimental animals, it was found that EGb 761® (definition see editorial) shows beneficial effects both on brain glucose and energy metabolism and on behavior.

References

  • 1 Biesold D, Inanami O, Sato A, Sato Y. Stimulation of the nucleus basalis of Meynert increases cerebral cortical blood flow in rats.  Neurosci Lett. 1989;  98 39-44
    CrossrefPubMedGoogle Scholar
  • 2 Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal Ch AT activity in rats after an icv injection of streptozotocin.  Pharmacol Biochem Behav. 1993;  44 491-494
    CrossrefPubMedGoogle Scholar
  • 3 Blokland A, Jolles J. Behavioral and biochemical effects of an icv injection of streptozotocin in old Lewis rats.  Pharmacol Biochem Behav. 1994;  47 833-837
    CrossrefPubMedGoogle Scholar
  • 4 Burnstock G. Overview. Purinergic mechanisms.  Ann NY Acad Sci. 1990;  603 1-17
    PubMedGoogle Scholar
  • 5 Bush M L, Niyashiro J S, Ingram V M. Activation of a neurofilament kinase, a tau kinase and tau phosphatase by decreased ATP levels in nerve growth factor-differentiated PC 12 cells.  Proc Natl Acad Sci USA. 1995;  92 1962-1965
    PubMedGoogle Scholar
  • 6 Coyle J T, Donald L P, Delong M R. Alzheimer’s disease: a disorder of cortical cholinergic innervation.  Science. 1983;  219 1184-1186
    PubMedGoogle Scholar
  • 7 Davies P, Maloney A JR. Selective loss of central cholinergic neurons in Alzheimer’s disease.  Lancet. 1976;  2 1403-1405
    PubMedGoogle Scholar
  • 8 DeFeudis F V editor. Ginkgo biloba extract (Egb-761). From chemistry to clinic. Wiesbaden; Ullstein Medical 1998
    Google Scholar
  • 9 Drachman D A, Noffsinger D, Sahakian B J, Kurdziel S, Fleming P. Aging, memory and the cholinergic system: a study of dichotic listening.  Neurobiol Aging. 1980;  1 39-43
    CrossrefPubMedGoogle Scholar
  • 10 Duelli R, Schröck H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats.  Int J Dev Neurosci. 1994;  12 737-743
    PubMedGoogle Scholar
  • 11 Frölich L, Blum-Degen D, Bernstein H G, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheiner A, Türk A, Hoyer S. et al . Insulin and insulin receptors in the brain in aging and sporadic Alzheimer’s disease.  J Neural Transm. 1998;  105 423-438
    Google Scholar
  • 12 Gasparini L, Gouras G K, Wang R, Gross R S, Beal M F, Greengard P, Xu H. Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling.  J Neurosci. 2001;  21 2561-2570
    CrossrefPubMedGoogle Scholar
  • 13 Gibson G E, Jope R, Blass J P. Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces.  Biochem J. 1975;  148 17-23
    PubMedGoogle Scholar
  • 14 Gibson G E, Peterson C, Jenden D J. Brain acetylcholine synthesis declines with senescence.  Science. 1981;  213 673-676
    PubMedGoogle Scholar
  • 15 Giorgino F, Almahfouz A, Goodyear L J, Smith R J. Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal mucle in vivo.  J Clin Invest. 1993;  91 2020-2030
    CrossrefPubMedGoogle Scholar
  • 16 Gouras G K, Tsai J, Naslund J, Vincent B, Edgar M, Greenfield J P, Haroutunian V, Buxbaum J D, Xu H, Greengard P, Relkin N R. Intraneural Aβ42 accumulation in human brain.  Am J Pathol. 2000;  156 15-20
    PubMedGoogle Scholar
  • 17 Guzowski F, Lyford G L, Stevenson G D, Houston F, McGaugh J L, Worley P F, Barnes C A. Inhibition of activity dependent ARC protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.  J Neurosci. 2000;  20 3993-4001
    PubMedGoogle Scholar
  • 18 Häring H. The insulin receptor: signaling mechanism and contribution to the pathogenesis of insulin restistance.  Diabetologia. 1991;  34 848-861
    CrossrefPubMedGoogle Scholar
  • 19 Hellweg R, Nitsch R, Hock C, Jaksch M, Hoyer S. Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism.  J Neurosci Res. 1992;  31 479-486
    CrossrefPubMedGoogle Scholar
  • 20 Henneberg N, Hoyer S. Short-term or long-term intracerebroventricular (i. c. v.) infusion oí insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat.  Neurosci Lett. 1994;  175 153-156
    CrossrefPubMedGoogle Scholar
  • 21 Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)?.  Arch Gerontol Geriat. 1995;  21 63-74
    PubMedGoogle Scholar
  • 22 Hong M F, Lee V MY. Insulin and insulin-like growth factor- 1 regulate tau phosphorylation in cultured human neurons.  J Biol Chem. 1997;  272 19 547-19 553
    PubMedGoogle Scholar
  • 23 Hoyer S. Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases.  Mol Chem Neuropathol. 1992;  16 207-224
    PubMedGoogle Scholar
  • 24 Hoyer S. Oxidative metabolism deficiencies in brain of patients with Alzheimer’s disease.  ActaNeurol Scand Suppl. 1996;  165 18-24
    PubMedGoogle Scholar
  • 25 Hoyer S. Is sporadic Alzheimer’s disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis.  J Neural Transm. 1998;  105 415-422
    CrossrefPubMedGoogle Scholar
  • 26 Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer’s disease. Causes and consequences: An update. Exp.  Gerontol. 2000;  35 1363-1372
    PubMedGoogle Scholar
  • 27 Hoyer S. The brain insulin signal transduction system and sporadic (type II) Alzheimer’s disease: An update.  J Neural Transm. 2002;  109 341-360
    CrossrefPubMedGoogle Scholar
  • 28 Hoyer S, Lannert H, Nöldner M, Chatterjee S S. Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761).  J Neural Transm. 1999;  106 1171-1188
    CrossrefPubMedGoogle Scholar
  • 29 Hoyer S, Prem L, Sorbi S, Amaducci L. Stimulation of glycolytic key enzymes in cerebral cortex by insulin.  NeuroReport. 1993;  4 991-993
    PubMedGoogle Scholar
  • 30 Huganir R L, Greengard P. Regulation of neurotransmitter receptor desensitization by protein phosphorylation.  Neuron. 1990;  5 555-567
    CrossrefPubMedGoogle Scholar
  • 31 Ishida A, Furukawa K, Keller J N, Mattson M P. Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices.  NeuroReport. 1997;  8 2133-2137
    PubMedGoogle Scholar
  • 32 Kadowaki T, Kasuga M, Akanuma Y, Ezaki O, Takaku F. Decreased autophosphorylation of the insulin receptor-kinase in streptozotocin diabetic rats.  J Biol Chem. 1984;  259 14 208-14 216
    PubMedGoogle Scholar
  • 33 Kremerskothen H, Wendholt D, Teber I, Barnekow A. Insulin-induced expression of the activity-regulated cytoskeleton-associated gene (ARC) in human neuroblastoma cells requires p21ras, mitogen-activated protein kinase/extracellular regulated kinase and src tyrosine kinases but is protein kinase C-independent.  Neurosci Lett. 2002;  321 153-156
    PubMedGoogle Scholar
  • 34 Kyriakis J M, Hausman R E, Peterson S W. Insulin stimulates choline acetyltransferase activity in cultured embryonic chicken retina neurons.  Proc Natl Acad Sci USA. 1987;  84 7463-7467
    PubMedGoogle Scholar
  • 35 Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats.  Behav Neurosci. 1998;  112 1199-1208
    CrossrefPubMedGoogle Scholar
  • 36 Löffler T, Lee S K, Nöldner M, Chatterjee S S, Hoyer S. Schliebs R. Effect of Ginkgo biloba extract (EGb 761®) on glucose metabolism-related markers in streptozotocin- damaged rat brain.  J Neural Transm. 2001;  108 1457-1474
    CrossrefPubMedGoogle Scholar
  • 37 Luo Y, Sunderland T, Wolozin B. Physiological levels of β-amyloid activate phosphatidyl inositol 3-kinase with the involvement of tyrosine phosphorylation.  J Neurochem. 1996;  67 978-987
    PubMedGoogle Scholar
  • 38 Mandelkow E M, Drews G, Biernat J, Gustke N, van Lint J, Vandenheede J R, Mandelkow E. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau.  FEBS Lett. 1992;  314 315-321
    CrossrefPubMedGoogle Scholar
  • 39 Mattson M P. Secreted forms of β-amyloid precursor protein modulate dendritic outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons.  J Neurobiol. 1994;  25 439-450
    CrossrefPubMedGoogle Scholar
  • 40 Mayer G, Nitsch R, Hoyer S. Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats.  Brain Res. 1990;  532 95-100
    CrossrefPubMedGoogle Scholar
  • 41 Meziane H, Dodart J C, Mathis C, Little S, Clemens J, Paul S M, Ungerer A. Memory- enhancing effects of secreted forms of the beta-aymloid precursor protein in normal and amnestic mice.  Proc Natl Acad Sci USA. 1998;  95 12 683-12 688
    PubMedGoogle Scholar
  • 42 Nitsch R, Hoyer S. Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex.  Neurosci Lett. 1991;  128 199-202
    PubMedGoogle Scholar
  • 43 Nitsch R M, Slack BE Wurtman R J, Growdon J H. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.  Science. 1992;  258 304-307
    PubMedGoogle Scholar
  • 44 Park C R. Cognitive effects of insulin in the central nervous system.  Neurosci Biobehav Rev. 2001;  25 3 11-323
    PubMedGoogle Scholar
  • 45 Perry E K. The cholinergic hypothesis: ten years on.  Br Med Bull. 1986;  42 63-69
    PubMedGoogle Scholar
  • 46 Plaschke K, Hoyer S. Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus.  Int J Dev Neurosci. 1993;  11 477-483
    PubMedGoogle Scholar
  • 47 Plaschke K, Müller D, Hoyer S. Effects of adrenalectomy and corticosterone substitution on glucose and glycogen metabolism in rat brain.  J Neural Transm. 1996;  103 89-100
    CrossrefPubMedGoogle Scholar
  • 48 Prickaerts J, Blokland A, Honig W, Meng F, Jolles J. Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-1-carnitine.  Brain Res. 1995;  674 142-146
    CrossrefPubMedGoogle Scholar
  • 49 Quirion R, Aubert I, Robitaille Y, Gauthier S, Araujo D M, Chabot J -G. Neurochemical deficits in pathological brain aging: specificity and possible relevance for treatment strategies.  Clin Neuropharmacol. 1990;  13 S73-80
    PubMedGoogle Scholar
  • 50 Roch J M, Masliah E, Roch-Levecq A C, Sundsmo M P, Otero D AC, Veinbergs I, Saitoh T. Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid β-A4 protein precursor.  Proc Natl Acad Sci USA. 1994;  91 7450-7454
    PubMedGoogle Scholar
  • 51 Röder H M, Ingram V M. Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios.  JNeurosci. 1991;  11 3325-3342
    PubMedGoogle Scholar
  • 52 Salehi A, Swaab D F. Diminished neuronal metabolic activity in Alzheimer’s disease.  J Neural Transm. 1999;  106 955-986
    CrossrefPubMedGoogle Scholar
  • 53 Seksek O, Biwersi J, Verkman A S. Direct measurement of trans-Golgi pH in living cells and regulation of second messengers.  J Biol Chem. 1995;  270 4967-4970
    CrossrefPubMedGoogle Scholar
  • 54 Selkoe D J. The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease.  Trends Cell Biol. 1998;  8 447-453
    CrossrefPubMedGoogle Scholar
  • 55 Sims N R, Bowen D M, Allen S J, Smith C CT, Neary D, Thomas D J, Davison A N. Presynaptic cholinergic dysfunction in patients with dementia.  J Neurochem. 1983;  40 503-509
    CrossrefPubMedGoogle Scholar
  • 56 Solano D C, Sironi M, Bonfini C, Solerte S B, Govoni S, Racchi M. Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway.  FASEB J. 2000;  14 1015-1022
    PubMedGoogle Scholar
  • 57 Stecher J, Müller W E, Hoyer S. Learninig abilities depend on NMDA-receptor densitiy in hippocampus in adult rats.  J Neural Transm. 1997;  104 281-289
    CrossrefPubMedGoogle Scholar
  • 58 Steward O, Wallace C S, Lyford G L, Worley P. Synaptic activation causes the mRNA for the IEG ARC to localize selectively near activated post-synaptic sites on dendrites.  Neuron. 1998;  21 741 -751
    CrossrefPubMedGoogle Scholar
  • 59 Suzuki N, Hardebo J E. The cerebrovascular parasympathetic innervation.  Cerebrovasc Brain Metab Rev. 1993;  5 33-46
    PubMedGoogle Scholar
  • 60 Uddman R, Edvinsson L. Neuropeptides in the cerebral circulation.  Cerebrovasc Brain Metab Rev. 1989;  1 230-252
    PubMedGoogle Scholar
  • 61 Verde C, Pascale M C, Martive G, Lotti L V, Torrisi H R, Helenius A, Bonatti S. Effect of ATP depletion and DTT on the transport of membrane proteins from the endoplasmic reticulum and the intermediate compartment to the Golgi complex.  Eur J Cell Biol. 1995;  67 267-274
    PubMedGoogle Scholar
  • 62 Wilson C A, Doms R W, Lee V MY. Intracellular APP processing and Aβ production in Alzheimer’s disease.  J Neuropathol Exp Neurol. 1999;  58 787-794
    PubMedGoogle Scholar
  • 63 Wurtman R J. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons.  Trends Neurosci. 1992;  15 117-122
    CrossrefPubMedGoogle Scholar
  • 64 Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon M J, Alkon D L. Brain insulin receptors and spatial memory.  J Biol Chem. 1999;  274 34 839-34 842
    PubMedGoogle Scholar

Dr. med. Siegfried Hoyer

Dept. of Pathochemistry and General Neurochemistry

Institute of Pathology of the University

Im Neuenheimer Feld 220/221

69120 Heidelberg

Germany

      >