Journal of Neural Transmission

, Volume 113, Issue 11, pp 1645–1658 | Cite as

Alois Alzheimer revisited: differences in origin of the disease carrying his name

  • K. Maurer
  • S. Hoyer


Based on the means of his time, Alois Alzheimer supposed that the disease, later carrying his name, is a disease of older age, and that the pathomorphological structures he described are due to disturbances in brain metabolism.

In this contribution, it is discussed which cellular metabolic abnormalities may be representative for age-related sporadic Alzheimer disease (SAD) the predominant form of SAD in contrast to the very rare hereditary early-onset form. In focus are disturbances in glucose/energy metabolism which involve the deficits in acetylcholine, cholesterol and UDP-N-acetylglucosamine beside ATP. Another leading abnormality is the defect in cell membrane composition. The interrelation between abnormal glucose/energy metabolism and membrane defect may be assumed to form the basis for the induction of both the perturbed metabolism of the amyloid precursor protein leading to increased formation of β-amyloid and hyperphosphorylation of tau-protein destroying cell structures.

Alois Alzheimer may have been so prescient to assume most of this 100 years ago.

Keywords: Sporadic Alzheimer disease, history, brain, nutrition, energy metabolism, membranes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abad-Rodriguez, J, Ledesma, MJ, Craessaerts, K, Perga, S, Medina, M, Delacourte, A, Dingwall, C, de Strooper, B, Dossi, CG 2004Neuronal membrane cholesterol loss enhances amyloid peptide generationJ Cell Biol167953960PubMedGoogle Scholar
  2. Abbott, MA, Wells, DG, Fallon, JR 1999The insulin receptor tyrosine kinase substrate p 58/53 and the insulin receptor are components of CNS synapsesJ Neurosci1973007308PubMedGoogle Scholar
  3. Adamo, M, Raizada, MK, Le Roith, D 1989Insulin and insulin-like growth factor receptors in the nervous systemMol Neurobiol371100PubMedGoogle Scholar
  4. Airnaiz, E, Jelic, V, Almkvist, O, Wahlund, LO, Winblad, B, Valind, S, Nordberg, A 2001Impaired cerebral glucose and cognitive functioning predict deterioration in mild cognitive impairmentNeuroReport12851855Google Scholar
  5. Alessi, DR, Cohen, P 1998Mechanism of activation and function of protein kinase BCurr Opin Genet Dev85562PubMedGoogle Scholar
  6. Alzheimer, A 1907Über eine eigenartige Erkrankung der HirnrindeAllg Ztschr Psychiat64148149Google Scholar
  7. Alzheimer, A 1911Über eigenartige Krankheitsfälle des späteren AltersZtschr Ges Neurol Psychiat4356385Google Scholar
  8. Avruch, J 1998Insulin signal transduction through protein kinase cascadesMol Cell Biochem1823148PubMedGoogle Scholar
  9. Bak, P, Tang, C, Wiesenfeld, K 1988Self-organized criticalityPhys Rev A38365374Google Scholar
  10. Banks, WA 2004The source of cerebral insulinEur J Pharmacol490512PubMedGoogle Scholar
  11. Belanoff, JK, Gross, K, Yager, A, Schatzberg, AF 2001Corticosteroids and cognitionJ Psychiatric Res35127145Google Scholar
  12. Bigl, M, Beck, M, Bleyl, AD, Bigl, V, Eschrich, K 2000Altered phosphofructokinase mRNA levels but unchanged isoenzyme pattern in brains from patients with Alzheimer’s diseaseMol Brain Res76411414PubMedGoogle Scholar
  13. Bigl, M, Bleyl, AD, Zedlick, D, Arendt, T, Bigl, V, Eschrich, K 1996Changes of activity and isoenzyme pattern of phosphofructokinase in the brains of patients with Alzheimer’s diseaseJ Neurochem6711641171PubMedCrossRefGoogle Scholar
  14. Bigl, M, Brückner, MK, Arendt, T, Bigl, V, Eschrich, K 1999Activities of key glycolytic enzymes in the brains of patients with Alzheimer’s diseaseJ Neural Transm100499511Google Scholar
  15. Björkhem, I, Lütjohann, D, Diczfalusy, U, Stahle, L, Ahlborg, G, Wahren, J 1998Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulationJ Lipid Res3915941600PubMedGoogle Scholar
  16. Blass, JP, Gibson, GE, Hoyer, S 2002The role of the metabolic lesion in Alzheimer’s diseaseJ Alzheimers Dis4225232PubMedGoogle Scholar
  17. Blusztajn, KJ, Lopez Gonzales-Coviella, I, Logue, M, Growdon, JH, Wurtman, RJ 1990Levels of phospholipids catabolic intermediates, glycerophosphocholine and glycerophosphoethanolamine, are elevated in brains of Alzheimer’s disease but not of Down’s syndrome patientsBrain Res536240244PubMedGoogle Scholar
  18. Braakman, I, Helenius, J, Helenius, A 1992Role of ATP and disulfide bonds during protein folding in the endoplasmic reticulumNature356260262PubMedGoogle Scholar
  19. Brown, GG, Levine, SR, Gorell, JM, Pettegrew, JW, Gdowski, JE, Bueri, JA, Helpern, JA, Welch, KMA 1989In vitro31 P-NRM profiles of Alzheimer disease and multiple subcortical infarct dementiaNeurology3914231427PubMedGoogle Scholar
  20. Bubber, P, Haroutunian, V, Fisch, G, Blass, JP, Gibson, GE 2005Mitochondrial abnormalities in Alzheimer brain: mechanistic implicationsAnn Neurol57695703PubMedGoogle Scholar
  21. Bucht, G, Adolfsson, R, Lithner, F, Winblad, B 1983Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer typeActa Med Scand213387392PubMedCrossRefGoogle Scholar
  22. Buse, MG, Robinson, KA, Marshall, BA, Hresko, RC, Mueckler, MM 2002Enhanced O-GlcNAc protein modification is associated with insulin resistance in GLUT1-overexpressing musclesAm J Physiol Endocrinol Metab283E241E250PubMedGoogle Scholar
  23. Comer, FI, Hart, GW 2001Reciprocity between O-GlcNAc and O-phosphate on the carboxyl terminal domain of RNA polymerase IIBiochemistry4078457852PubMedGoogle Scholar
  24. Convit, A, Wolf, OT, Tarshish, C, DeLeon, MJ 2003Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderlyProc Natl Acad Sci USA10020192022PubMedGoogle Scholar
  25. Craft, S, Asthana, S, Schellenberg, G, Cherrier, M, Baker, LD, Newcomer, J, Plymate, S, Latendresse, S, Petrova, A, Raskind, J, Peskind, E, Lofgren, C, Grimwood, K 1999Insulin metabolism in Alzheimer’s disease differs according to apolipoprotein E genotype and genderNeuroendocrinology70146152PubMedGoogle Scholar
  26. Craft, S, Peskind, E, Schwartz, MW, Schellenberg, GD, Raskind, M, Porte, D,Jr 1998Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotypeNeurology50164168PubMedGoogle Scholar
  27. Cross, DA, Watt, PW, Shaw, M, von der Kaay, J, Downes, CP, Holder, JC, Cohen, P 1997Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-sensitive pathways in skeletal muscle and adipose tissueFEBS Lett406211215PubMedGoogle Scholar
  28. Cross, DAE, Alessi, DR, Cohen, P, Andjelkovich, M, Hemmings, BA 1995Inhibition of glycogen synthase kinase-3 by insulin mediated protein kinaseNature378785789PubMedGoogle Scholar
  29. Cutler, RG, Kelly, J, Storie, K, Pedersen, WA, Tammara, A, Hatanpaa, K, Troncorso, JC, Mattson, PT 2004Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s diseaseProc Natl Acad Sci USA10120702075PubMedGoogle Scholar
  30. D’Andrea, MR, Nagele, RG, Wang, HY, Peterson, PA, Lee, DHS 2001Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s diseaseHistopathology38120134PubMedGoogle Scholar
  31. Dastur, DK 1985Cerebral blood flow and metabolism in normal aging, pathological aging, and senile dementiaJ Cereb Blood Flow Metab9219Google Scholar
  32. Davis, KL, Davis, BM, Greenwald, BS, Mohs, RC, Mathé, AA, Johns, CA, Horvath, TB 1986Cortisol and Alzheimer’s disease. I: Basal studiesAm J Psychiatry143300305PubMedGoogle Scholar
  33. de Bruin, VMS, Vieira, MCM, Rocha, MNM, Viana, GSP 2002Cortisol and dehydroepiandrosterstone sulphate plasma levels and their relationship to aging, cognitive function, and dementiaBrain Cogn50316323PubMedGoogle Scholar
  34. Demaurex, N, Furuya, W, D’Souza, S, Bonifacino, JS, Grinstein, S 1998Mechanism of acidification of the trans-Golgi network (TGN). In situ measurements of pH using retrieval of TGN 38 and furin from the cell surfaceJ Biol Chem27320442051PubMedGoogle Scholar
  35. de Quervain, DJ, Poirsier, R, Wollmer, MA, Grimaldi, LM, Tsolaki, M, Streffer, JR, Hock, C, Nitsch, RM, Mohajeri, MH, Papassotiropoulos, A 2004Glucocorticoid-related genetic susceptibility for Alzheimer’s diseaseHum Mol Genet134752PubMedGoogle Scholar
  36. Devaskar, JU, Giddings, SJ, Rajakumar, PA, Carnaghi, LR, Menon, RK, Zahn, DS 1994Insulin gene expression and insulin synthesis in mammalian neuronal cellsJ Biol Chem26984458454PubMedGoogle Scholar
  37. Dietschy, JM, Turley, SD 2004Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animalJ Lipid Res4513751397PubMedGoogle Scholar
  38. Distl, R, Meske, V, Ohm, TG 2001Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neuronsActa Neuropathol101547554PubMedGoogle Scholar
  39. Dorner, AJ, Wasley, LC, Kaufman, RJ 1990Protein dissociation from GRP 78 and secretion are blocked by depletion of cellular ATP levelsProc Natl Acad Sci USA8774297432PubMedGoogle Scholar
  40. Drachman, DA, Noffsinger, D, Sahakian, BJ, Kurdziel, S, Fleming, P 1980Aging, memory and the cholinergic system: a study of dichotic listeningNeurobiol Aging13943PubMedGoogle Scholar
  41. Duara, R, Grady, C, Haxby, J, Sundaram, S, Cutler, NR, Heston, L, Moore, A, Schlageter, N, Larson, R, Rapoport, SI 1986Positron emission tomography in Alzheimer’s diseaseNeurology36879887PubMedGoogle Scholar
  42. Eckert, GP, Cairns, NJ, Maras, A, Gattaz, WF, Müller, WE 2000Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: specific changes in Alzheimer’s diseaseDement Geriatr Cogn Disord11181186PubMedGoogle Scholar
  43. Erecinska, M, Silver, IA 1989ATP and brain functionJ Cereb Blood Flow Metab9219PubMedGoogle Scholar
  44. Evans, DA, Funkenstein, H, Albert, MS, Scherr, PA, Cook, NR, Chown, MJ, Hebert, LE, Hennekens, CH, Taylor, JO 1989Prevalence of Alzheimer’s disease in a common population of older persons: higher than previously reportedJ Am Med Assoc26225512556Google Scholar
  45. Farris, W, Mansourian, S, Chang, Y, Lindsay, L, Eckman, EA, Frosch, MP, Eckman, CB, Tanzi, RE, Selkoe, DE, Guenette, S 2003Insulin-degrading enzyme regulates the levels of insulin, amyloid-β protein and the β-amyloid precursor protein intracellular domain in vivoProc Natl Acad Sci USA10041624167PubMedGoogle Scholar
  46. Foster, NL, Chase, TN, Mansi, K, Brooks, R, Fedio, P, Patronas, NJ, DiChiro, G 1984Cortical abnormalities in Alzheimer’s diseaseAnn Neurol16649654PubMedGoogle Scholar
  47. Frölich, L 2002The cholinergic pathology in Alzheimer’s disease – discrepancies between clinical experience and pathophysiological findingsJ Neural Transm10910031014PubMedGoogle Scholar
  48. Frölich, L, Blum-Degen, D, Bernstein, HG, Engelsberger, S, Humrich, J, Laufer, S, Muschner, D, Thalheimer, A, Türk, A, Hoyer, S,  et al. 1998Insulin and insulin receptors in the brain in aging and sporadic Alzheimer’s diseaseJ Neural Transm105423438PubMedGoogle Scholar
  49. Fukuyama, H, Ogawa, M, Yamauchi, H, Yamaguchi, S, Kimura, J, Yonekura, Y, Konishi, J 1994Altered cerebral energy metabolism in Alzheimer’s disease: a PET studyJ Nucl Med3516PubMedGoogle Scholar
  50. Gasparini, L, Gouras, GK, Wang, R, Gross, RS, Beal, MF, Greengard, P, Xu, H 2001Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneural β-amyloid and requires mitogen-activated protein kinase signallingJ Neurosci2125612570PubMedGoogle Scholar
  51. Gattaz, WF, Maras, A, Cairns, NJ, Levy, R, Förstl, H 1995Decreased phospholipase A2 activity in Alzheimer brainsBiol Psychiatry371317PubMedGoogle Scholar
  52. Gaudreault, SB, Dea, D, Poirier, J 2004Increased caveolin-1 expression in Alzheimer’s disease brainNeurobiol Aging25753759PubMedGoogle Scholar
  53. Gething, MJ, Sambrook, J 1992Protein folding in the cellNature3553345PubMedGoogle Scholar
  54. Gibbs, EL, Lennox, WG, Nims, LF, Gibbs, FA 1942Arterial and cerebral venous blood: arterial venous differences in manJ Biol Chem114325332Google Scholar
  55. Gibson, GE, Jope, R, Blass, JP 1975Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain mincesBiochem J1481723PubMedGoogle Scholar
  56. Giorgino, F, Almahfouz, A, Goodyear, LJ, Smith, RJ 1993Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivoJ Clin Invest9120202030PubMedCrossRefGoogle Scholar
  57. Goldstein, BJ 1993Regulation of insulin receptor signalling by protein-tyrosine dephosphorylationReceptor3115PubMedGoogle Scholar
  58. Gong, CX, Liu, F, Grundke-Iqbal, I, Iqbal, K 2006Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-Glc NAcylationJ Alzheimers Dis9112PubMedGoogle Scholar
  59. Gottstein, U, Bernsmeier, A, Sedlmeyer, I 1963Der Kohlenhydratstoffwechsel des menschlichen Gehirns. I. Untersuchungen mit substratspezifischen enzymatischen Methoden bei normaler HirndurchblutungKlin Wschr41943948PubMedGoogle Scholar
  60. Gouras, GK, Tsai, J, Naslund, J, Vincent, B, Edgard, M, Greenfield, JP, Haroutunian, V, Buxbaum, JS, Xu, H, Greengard, P, Relkin, NR 2000Intraneuronal βA-41 accumulation in human brainAm J Pathol1561520PubMedGoogle Scholar
  61. Hardy, J, Selkoe, DJ 2002The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road of therapeuticsScience297353356PubMedGoogle Scholar
  62. Häring, HU, Kirsch, D, Obermeier, B, Ermel, B, Machicao, F 1986Decreased tyrosine kinase activity of insulin receptor isolated from rat adipocytes rendered insulin-resistant by catecholamine treatment in vitroBiochem J2345966PubMedGoogle Scholar
  63. Hart, GW 1997Dynamic O-linked glycosylation of nuclear and cytoskeletal proteinsAnnu Rev Biochem66315335PubMedGoogle Scholar
  64. Heidenreich, KA, Zahniser, NR, Berhanu, P, Brandenburg, D, Olefsky, JM 1983Structural differences between insulin receptors in the brain and peripheral target tissuesJ Biol Chem25885278530PubMedGoogle Scholar
  65. Held, GA, Solina, DH, Keane, DT, Haag, WJ, Horn, PM, Grinstein, G 1990Experimental study of critical-mass fluctuations in an evolving sandpilePhysic Rev Lett6911201123Google Scholar
  66. Henneberg, N, Hoyer, S 1994Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the ratNeurosci Lett175153156PubMedGoogle Scholar
  67. Herholz, K, Salmon, E, Perani, D, Baron, DJ, Holthoff, V, Frölich, L, Schönknecht, P, Ito, K, Mielke, R, Kalbe, E,  et al. 2002Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDGPETNeuroImage17302316PubMedGoogle Scholar
  68. Hess, B 1983Non-equilibrium dynamics of biochemical processesHoppe-Seylers Z Physiol Chem364120PubMedGoogle Scholar
  69. Hess, B 1990Order and chaos in chemistry and biologyFresenius J Anal Chem337459468Google Scholar
  70. Hirata, F, Axelrod, J 1980Phospholipid methylation and biological signal transmissionScience20910821090PubMedGoogle Scholar
  71. Hollness, MH, Langdown, ML, Sugden, MC 2000Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of type 2 diabetes mellitusBiochem J349657665Google Scholar
  72. Hong, MF, Lee, VMY 1997Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neuronsJ Biol Chem2721954719553PubMedGoogle Scholar
  73. Hoogendijk, WJG, Feenstra, MGP, Botterblom, MHA, Gilhuis, J, Sommer, IEC, Kamphorst, W, Eikelenboom, P, Swaab, DF 1999Increased activity of surviving locus ceruleus neurons in Alzheimer’s diseaseAnn Neurol458291PubMedGoogle Scholar
  74. Hoyer, S 1970Der Aminosäurenstoffwechsel des normalen menschlichen GehirnsKlin Wschr4812391243PubMedGoogle Scholar
  75. Hoyer, S 1986Senile dementia and Alzheimer’s disease: Brain blood flow and metabolismProg Neuropsychopharmacol Biol Psychiatry10447478PubMedGoogle Scholar
  76. Hoyer, S 1992Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset casesMol Chem Neuropathol16207224PubMedCrossRefGoogle Scholar
  77. Hoyer, S 1998Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis:J Neural Transm105415422PubMedGoogle Scholar
  78. Hoyer, S, Plaschke, K 2004The aging brain. The burden of life (?)Herdegen, TDelgado Garcia, J eds. Brain damage and repair.KluwerDordrecht122Google Scholar
  79. Hoyer, S, Nitsch, R, Oesterreich, K 1991Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer-type: a cross-sectional comparison against advanced late-onset dementia and incipient early-onset casesJ Neural Transm (PD-Sect)3114Google Scholar
  80. Hoyer, S, Prem, L, Sorbi, S, Amaducci, L 1993Stimulation of glycolytic key enzymes in cerebral cortex by insulinNeuroReport4991993PubMedGoogle Scholar
  81. Igbavboa, U, Avdulov, NA, Schröder, F, Wood, WG 1996Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of miceJ Neurochem6617171725PubMedCrossRefGoogle Scholar
  82. Ishiguro, K, Shiratsuchi, A, Sato, S, Omori, A, Arioka, M, Kobayashi, S, Uchida, T 1993Glycogen synthase kinase 3-beta is identical to tau protein kinase I generating several epitopes of paired helical filamentsFEBS Lett325167172PubMedGoogle Scholar
  83. Joseph, J, Shukitt-Hale, B, Denisova, NA, Martin, A, Perry, G, Smith, MA 2001Copernicus revisited: amyloid beta in Alzheimer’s diseaseNeurobiol Aging22131146PubMedGoogle Scholar
  84. Kadekaro, N, Crane, AM, Sokoloff, L 1985Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the ratProc Natl Acad Sci USA8260106013PubMedGoogle Scholar
  85. Kakio, A, Nishimoto, S, Yanagisawa, K, Kozutsumi, Y, Matsuzaki, K 2001Cholesterol-dependent formation of GM1 ganglioside-bound amyloid-β-protein, an endogenous seed for Alzheimer amyloidJ Biol Chem2762498524990PubMedGoogle Scholar
  86. Kaufman, RJ 1999Stress signalling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controlsGenes Dev1312111233PubMedGoogle Scholar
  87. Kauppinen, RA, Nichols, DG 1986Failure to maintain glycolysis in anoxic nerve terminalJ Neurochem4718641869PubMedGoogle Scholar
  88. Keller, JN, Pang, Z, Geddes, JW, Begley, JG, Germeyer, A, Waeg, G, Mattson, MP 1997Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β-peptide: role of the lipid peroxidation product 4-hydroxynonenalJ Neurochem69273284PubMedCrossRefGoogle Scholar
  89. Kirsch, C, Eckert, GP, Koudinov, AR, Müller, WE 2003Brain cholesterol, statins and Alzheimer’s diseasePharmacopsychiatry36S113S119PubMedGoogle Scholar
  90. Kirsch, C, Eckert, GP, Mueller, WE 2002Cholesterol attenuates the membrane perturbing properties of β-amyloid peptidesAmyloid9149159PubMedGoogle Scholar
  91. Klein, J 2000Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipidsJ Neural Transm10710271063PubMedGoogle Scholar
  92. Kliegel, M, Rott, C, d’Heureuse, V, Becker, G, Schönemann, P 2001Dementia in the very old is not a necessity: results from the Heidelberg Centenarian StudyZ Gerontopsychol-psychiatrie14169180Google Scholar
  93. Kurochkin, IV, Goto, S 1994Alzheimer’s beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzymeFEBS Lett3453337PubMedGoogle Scholar
  94. Kyriakis, JM, Hausman, RE, Peterson, SW 1987Insulin stimulates choline acetyltransferase activity in cultured embryonic chicken retina neuronsProc Natl Acad Sci USA8474637467PubMedGoogle Scholar
  95. Ledesma, MD, Abad-Rodriguez, J, Galvan, C, Biondi, E, Navarro, P, Delacourte, A, Dingwall, C, Dotti, CG 2003Raft disorganization leads to reduced plasmin activity in Alzheimer’s disease brainsEMBO Rep411901196PubMedGoogle Scholar
  96. Ledesma, MD, Da Silva, JS, Schevchenko, A, Wilm, M, Dotti, CG 2003Proteonic characterization of neuronal sphingolipid-cholesterol microdomains: role in plasminogen activationBrain Res987107116PubMedGoogle Scholar
  97. Lesort, M, Jope, RS, Johnson, GVW 1999Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3β and Fyen tyrosine kinaseJ Neurochem72576584PubMedGoogle Scholar
  98. Liscum, L, Munn, NJ 1999Intracellular cholesterol transportBiochim Biophys Acta14381937PubMedGoogle Scholar
  99. Lütjohann, D, Breuer, O, Ahlborg, G, Nennesmo, I, Siden, A, Diczfalusy, U, Björkhem,  1996Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24 S-hydroxysterol from the brain into the circulationProc Natl Acad Sci USA9397999804PubMedGoogle Scholar
  100. Mahley, RW, Rall, SC,Jr 2000Apolipoprotein E: far more than a lipid transport proteinAnnu Rev Genom Hum Genet1507537Google Scholar
  101. Mandelkow, EM, Drewes, G, Biernet, J, Gustke, N, van Lint, J, Vandeenheede, JR, Mandelkow, E 1992Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tauFEBS Lett314215221Google Scholar
  102. Mason, RP, Shoemaker, WJ, Shajenko, L, Chambers, TE, Herbette, LG 1992Evidence for changes in the Alzheimer’s disease brain cortical membrane structure mediated by cholesterolNeurobiol Aging13413419PubMedGoogle Scholar
  103. Mastrogiacomo, F, Bergeron, C, Kish, SJ 1993Brain α-ketoglutarate dehydrogenase complex activity in Alzheimer’s diseaseJ Neurochem6120072014PubMedGoogle Scholar
  104. Mauch, DH, Nägler, J, Schumacher, S, Göritz, EC, Otto, A, Pfrieger, FW 2001CNS synaptogenesis promoted by glia-derived cholesterolScience29413541357PubMedGoogle Scholar
  105. McDermott, JR, Gibson, AM 1997Degradation of Alzheimer’s beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzymeNeurochem Res224956PubMedGoogle Scholar
  106. McLaurin, J, Chakrabartty, A 1996Membrane disruption by Alzheimer β-amyloid peptides mediated through specific binding to either phospholipids or gangliosidesJ Biol Chem2712648226489PubMedGoogle Scholar
  107. McLaurin, J, Franklin, T, Fraser, PE, Chakrabartty, A 1998Structural transitions associated with the interaction of Alzheimer β-amyloid peptides with gangliosidesJ Biol Chem27345064515PubMedGoogle Scholar
  108. Michikawa, M, Yanagisawa, K 1999Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell deathJ Neurochem7222782285PubMedGoogle Scholar
  109. Mielke, R, Herholz, K, Grond, M, Heiss, WD 1994Clinical deterioration in probable Alzheimer’s disease correlates with progressive metabolic impairment of association areasDementia53641PubMedGoogle Scholar
  110. Minoshima, S, Giordani, B, Berent, S, Frey, KA, Kuhl, DE 1997Metabolic reduction in the posterior cingulated cortex in very early Alzheimer’s diseaseAnn Neurol428594PubMedGoogle Scholar
  111. Mirollo, RE, Strogatz, SH 1990Synchronization of pulse-coupled biological oscillatorsSIAM J Appl Math5016451649Google Scholar
  112. Molander-Melin, M, Blennow, K, Bogdanovic, N, Dellheden, B, Mansson, JE, Fredman, P 2005Structural membrane alterations in Alzheimer brains found to be associated with regional disease development, increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent-resistant membrane domainsJ Neurochem92171182PubMedGoogle Scholar
  113. Nitsch, RM, Busztajin, JK, Pittas, AG, Slack, BE, Growdon, JH, Wurtman, RJ 1992bEvidence for a membrane defect in Alzheimer’s disease brainProc Natl Acad Sci USA8916711675Google Scholar
  114. Nitsch, RM, Slack, BE, Wurtman, RJ, Growdon, J 1992aRelease of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptorsScience258304307Google Scholar
  115. Ott, A, Breteler, MMB, van Harskamp, F, Clauss, JJ, van der Cammen, THM, Grobbee, DE, Hofman, A 1995Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam studyBr J Med310970973Google Scholar
  116. Parker, WD, Parks, J, Filly, CM, Kleinschmidt-DeMasters, BK 1994Electron transport chain defects in Alzheimer’s disease brainNeurology4410901096PubMedGoogle Scholar
  117. Parkin, ET, Turner, AJ, Hooper, NM 1999Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft proteinBiochem J3442330PubMedGoogle Scholar
  118. Paschen, W, Frandsen, A 2001Endoplasmic reticulum dysfunction – a common denominator for cell injury in acute and degenerative diseases of the brain?J Neurochem79719725PubMedGoogle Scholar
  119. Pascualy, M, Petrie, EC, Brodkin, K, Peskind, ER, Wilkinson, W, Raskind, MA 2000Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressure test in Alzheimer’s diseaseBiol Psychiatry48247254PubMedGoogle Scholar
  120. Perez, A, Morelli, L, Cresto, JC, Castano, EM 2000Degradation of soluble amyloid β-peptides 1–40, 1–42, and the Dutch variant 1–40Q by insulin degrading enzyme from Alzheimer disease and control brainNeurochem Res25247255PubMedGoogle Scholar
  121. Perry, EK, Perry, RG, Tomlinson, BE, Blessed, G, Gibson, PH 1980Coenzyme A-acetylating enzymes in Alzheimer’s disease: possible cholinergic “compartment” of pyruvate dehydrogenaseNeurosci Lett18105110PubMedGoogle Scholar
  122. Peskind, ER, Elrod, R, Dobie, DJ, Pascualy, M, Petrie, E, Jensen, R, Brodkin, K, Murray, S, Veith, RC, Raskind, MA 1998Cerebrospinal fluid epinephrine in Alzheimer’s disease and normal agingNeuropsychopharmacology19465471PubMedGoogle Scholar
  123. Peskind, ER, Wilkinson, CW, Schellenberg, EC, Raskind, MA 2001Increased CSF cortisol in AD is a function of APOE genotypeNeurology5610941098PubMedGoogle Scholar
  124. Peskind, ER, Wingerson, D, Murray, S, Pascualy, M, Dobie, DJ, LeCorre, P, LeVerge, R, Veith, RC, Raskind, MA 1995Effects of Alzheimer’s disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidineArch Gen Psychiatry52774782PubMedGoogle Scholar
  125. Petanceska, SS, Gandy, S 1999The phophatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer’s amyloid precursor proteinJ Neurochem7323162320PubMedGoogle Scholar
  126. Pettegrew, JW, Klunk, WE, Kanal, E, Panchalingam, K, McClure, RJ 1995Changes in brain membrane phospholipids and high-energy phosphate metabolism precede dementiaNeurobiol Aging16973975PubMedGoogle Scholar
  127. Pettegrew, JW, Moossy, J, Withers, G, McKeag, D, Panchalingam, K 198831P nuclear magnetic resonance study of the brain in Alzheimer’s diseaseJ Neuropathol Exp Neurol47235248PubMedGoogle Scholar
  128. Phiel, CJ, Wilson, CA, Lee, VMY, Klein, PS 2003GSK-3α regulates production of Alzheimer’s disease amyloid-β peptidesNature423435439PubMedGoogle Scholar
  129. Plata-Salaman, CR 1991Insulin in the cebebrospinal fluidNeurosci Biobehav Rev15243258PubMedGoogle Scholar
  130. Prigogine, I 1989What is entropy?Naturwissenschaften7618Google Scholar
  131. Procter, AW, Palmer, AM, Francis, PT, Lowe, SL, Neary, D, Murphy, E, Doshi, R, Bowen, DM 1988Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s diseaseJ Neurochem50790802PubMedGoogle Scholar
  132. Ramakrishna, S, Benjamin, WB 1998Insulin action rapidly decreases multifunctional protein kinase activity in rat adipose tissueJ Biol Chem2631267712681Google Scholar
  133. Rinaudo, MT, Curto, M, Bruno, R, Marino, C, Rossetti, V, Mostert, M 1987Evidence of an insulin generated pyruvate dehydrogenase stimulating factor in rat brain plasma membranesItal J Biochem19909913Google Scholar
  134. Rivera, EJ, Golding, A, Fulmer, N, Tavares, R, Wands, JR, de la Monte, SM 2005Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholineJ Alzheimers Dis8247268PubMedGoogle Scholar
  135. Röder, HM, Ingram, VM 1991Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratiosJ Neurosci1133253342PubMedGoogle Scholar
  136. Roher, AE, Weiss, N, Kokjohn, TA, Kuo, YM, Kalback, W, Anthony, J, Watson, D, Luehrs, DC, Sue, L, Walker, D, Emmerling, M, Goux, W, Beach, T 2002Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s diseaseBiochemistry411108011090PubMedGoogle Scholar
  137. Ross, BM, Moszczynska, A, Erlich, J, Kish, SJ 1998Phospholipid-metabolizing enzymes in Alzheimer’s disease: increased lysophospholipid acetyltransferase activity and decreased phospholipase A2 activityJ Neurochem70786793PubMedCrossRefGoogle Scholar
  138. Rossner, S, Weberham, U, Yu, J, Kirazor, L, Schliebs, R, Perez-Polo, JR, Bigl, V 1997In vivo regulation of amyloid precursor protein secretion in rat neocortex by cholinergic activityEur J Neurosci921252134PubMedGoogle Scholar
  139. Rothman, JE 1996The protein machinery of vesicle budding and fusionProtein Sci5185194PubMedCrossRefGoogle Scholar
  140. Rothman, JE, Orci, L 1992Molecular dissection of the secretory pathwayNature355409415PubMedGoogle Scholar
  141. Rothman, JE, Wielandt, FT 1996Protein sorting by transport vesiclesScience272227234PubMedGoogle Scholar
  142. Rupprecht, R, Holsboer, F 1999Neuroactive steroids: mechanism of action and neuropsychopharmacological perspectivesTrends Neurosci22410416PubMedGoogle Scholar
  143. Sacks, W 1957Cerebral metabolism of isotopic glucose in normal brain subjectsJ Appl Physiol103744PubMedGoogle Scholar
  144. Salkovic-Petrisic, M, Lackovic, Z 2005Insulin resistant brain state and its link to diabetes mellitusPeriod Biol107137146Google Scholar
  145. Salkovic-Petrisic, M, Tribl, F, Schmidt, M, Hoyer, S, Riederer, P 2006Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathwayJ Neurochem9610051015PubMedGoogle Scholar
  146. Sato, A, Sato, Y 1995Cholinergic neural regulation of regional cerebral blood flowAlzheimer Dis Ass Disord92838Google Scholar
  147. Schechter, R, Whitmire, J, Holtzclaw, L, George, M, Devaskar, JU 1992Developmental regulation of insulin in the mammalian central nervous systemBrain Res5822737PubMedGoogle Scholar
  148. Schroeder, F, Frolov, AA, Murphey, EJ, Atshaves, BP, Jefferson, RJ, Pu, LX, Wood, WG, Foxworth, WB, Kier, AB 1996Recent advances in membrane cholesterol domain dynamics and intracellular cholesterol traffickingProc Soc Exp Biol Med213150177PubMedGoogle Scholar
  149. Seckl, JR, Walker, BR 2001Minireview: 11 beta-hydroxysteroid dehydrogenase type 1-a tissue-specific amplifier of glucocorticoid actionEndocrinology14213711376PubMedGoogle Scholar
  150. Seksek, O, Biwersi, J, Verkman, AS 1995Direct measurement of trans-Golgi pH on living cells and regulation by second messengersJ Biol Chem27049674970PubMedGoogle Scholar
  151. Siesjö BK (1978) Brain energy metabolism. Wiley, Chichester, pp 56–100, 281–284Google Scholar
  152. Simons, K, Toomre, D 2000Lipid rafts and signal transductionNat Rev Mol Cell Biol13139PubMedGoogle Scholar
  153. Sims, NR, Bowen, DM, Allen, SJ, Smith, CCT, Neary, D, Thomas, DJ, Davison, AN 1983aPresynaptic cholinergic dysfunction in patients with dementiaJ Neurochem40503509Google Scholar
  154. Sims, NR, Bowen, DM, Neary, D, Davison, AN 1983bMetabolic processes in Alzheimer’s disease: adenine nucleotide content and production of 14CO2 from (U14C) glucose in vivo in human neocortexJ Neurochem4113291334Google Scholar
  155. Singh, H, Usher, S, Poulos, A 1989Mitochondrial and peroxisomal beta-oxidation of stearic and lignoceric acids by rat brainJ Neurochem5317111718PubMedGoogle Scholar
  156. Söderberg, M, Edlund, C, Alafuzoff, I, Kristensson, K, Dallner, G 1992Lipid composition in different regions of the brain in Alzheimer’s disease/senile dementia of Alzheimer typeJ Neurochem5916461653PubMedGoogle Scholar
  157. Söderberg, M, Edlund, C, Kristensson, K, Dallner, G 1991Fatty acid composition of brain phospholipids in aging and in Alzheimer’s diseaseLipids26412425Google Scholar
  158. Sokoloff, L 1981Localization and functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucoseJ Cereb Blood Flow Metab1736PubMedGoogle Scholar
  159. Solano, DC, Sironi, M, Bonfini, C, Solarte, SB, Govoni, S, Racchi, M 2000Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathwayFASEB J1410151022PubMedGoogle Scholar
  160. Sorbi, S, Bird, ED, Blass, JP 1983Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brainAnn Neurol137278PubMedGoogle Scholar
  161. Spector, AA, Yorek, MA 1985Membrane lipid composition and cellular functionJ Lipid Res2610151035PubMedGoogle Scholar
  162. Steen, E, Terry, BM, Rivera, EJ, Cannon, JL, Neely, TR, Tavares, R, Xu, XJ, Wands, JR, de la Monte, SM 2005Impaired insulin and insulin-like growth factor expression and signalling mechanisms in Alzheimer’s disease – is this type 3 diabetes?J Alzheimers Dis76380PubMedGoogle Scholar
  163. Sun, FF, Fleming, WE, Taylor, BM 1993Degradation of membrane phospholipids in the cultured human astroglial cell line UC-11 MG during ATP depletionBiochem Pharmacol4511491155PubMedGoogle Scholar
  164. Svennerholm, L, Gottfries, CG 1994Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset from (type I) and demyelination in late-onset (type II)J Neurochem6210391047PubMedCrossRefGoogle Scholar
  165. Swaab, DF, Raadsheer, FC, Endert, EF, Hofman, MA, Kamphorst, WC, Ravid, R 1994Increases in cortisol levels in aging and Alzheimer’s disease in postmortem cerebrospinal fluidNeuroendocrinology6681687CrossRefGoogle Scholar
  166. Sweeney, G, Klip, A 1998Regulation of the Na+/K+ – ATPase by insulin: Why and how?Mol Cell Biochem182121133PubMedGoogle Scholar
  167. Tanzi, RE, Bertram, L 2001New frontiers in Alzheimer’s disease geneticsNeuron32181184PubMedGoogle Scholar
  168. Unger, J, McNeill, TH, Moxley, RT, White, M, Moss, A, Livingston, JN 1989Distribution of insulin receptor-like immunoreactivity in the rat forebrainNeuroscience31143157PubMedGoogle Scholar
  169. Vance, JE, Hayashi, H, Karten, B 2005Cholesterol homeostasis in neurons and glial cellsSemin Cell Dev Biol16193212PubMedGoogle Scholar
  170. Vanhaesebroeck, A, Alessi, DR 2000The PIK3K-PDK1 connection: more than just a road to PKBBiochem J346561576PubMedGoogle Scholar
  171. Vekrellis, K, Ye, Z, Qiu, WQ, Walsh, D, Hartle, D, Chesneau, U, Rosner, MR, Selkoe, DJ 2000Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzymeJ Neurosci2016571665PubMedGoogle Scholar
  172. Verde, C, Pascale, MC, Martive, G, Lotti, LV, Torrisi, MR, Helenius, A, Bonatti, S 1995Effect of ATP depletion and DTT on the transport of membrane proteins from the endoplasmic reticulum and intermediate compartment to the Golgi complexEur J Cell Biol67267274PubMedGoogle Scholar
  173. Wong, KL, Tyce, GM 1983Glucose and amino acid metabolism in rat brain during sustained hypoglycaemiaNeurochem Res8401415PubMedGoogle Scholar
  174. Wu, Y, Sun, FF, Tong, DM 1996Changes in membrane properties during energy depletion-induced cell injury studied with fluorescence microscopyBiophys J7191100PubMedCrossRefGoogle Scholar
  175. Yanagisawa, K, Ihara, Y 1998GM1 ganglioside-bound amyloid β-protein in Alzheimer’s disease brainNeurobiol Aging19S65S67PubMedGoogle Scholar
  176. Yanagisawa, K, Odaka, A, Suzuki, N, Ihara, Y 1995GM1 ganglioside- bound amyloid β-protein (Aβ): a possible form of preamyloid in Alzheimer’s diseaseNat Med110621066PubMedGoogle Scholar
  177. Yasojima, K, McGeer, EG, McGeer, PL 20013-hydroxy-3-methylglutaryl-coenzyme. A reductase mRNA in Alzheimer and control brainNeuro Report1229352938Google Scholar
  178. Yki-Jarvinen, H, Virkamaki, A, Daniels, MC, McClain, D, Gottschalk, WK 1998Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in skeletal muscle protein in vivoMetabolism47449455PubMedGoogle Scholar
  179. Zhang, H, Sternberger, NH, Rubinstein, LJ, Herman, MM, Binder, LI, Sternberger, LA 1989Abnormal processing of multiple proteins in Alzheimer’s diseaseProc Natl Acad Sci USA8680458049PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • K. Maurer
    • 1
  • S. Hoyer
    • 2
  1. 1.Clinic for PsychiatryUniversity of FrankfurtFrankfurt/MainGermany
  2. 2.Department of PathologyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations