Advertisement

Metabolic Abnormalities in Alzheimer Disease

  • Florian M. Gebhardt
  • Peter R. Dodd
Chapter

Abstract

In 1906, German neuropathologist and psychiatrist Alois Alzheimer described “eine eigenartige Erkrankung der Hirnrinde” (a peculiar disease of the cerebral cortex). Alzheimer noted two abnormalities in autopsied brain tissue from his index case: senile plaques, proteinaceous structures previously described in the brain of normal elderly people; and abnormal cells delineated with silver stain that became known as neurofibrillary tangles (NFTs). The distribution and abundance of tangle-filled neurons are now the main criteria used to diagnose Alzheimer disease (AD) at autopsy.

Keywords

Alzheimer Disease Dystrophic Neurites Alzheimer Disease Patient PP2A Activity Alzheimer Disease Brain 
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.

References

  1. Albin, R.L. Greenamyre, J.T. 1992. Alternative excitotoxic hypotheses. Neurology 42:733-738PubMedCrossRefGoogle Scholar
  2. Alves da Costa, C., Sunyach, C., Pardossi-Piquard, R., Sevalle, J., Vincent, B., Boyer, N., Kawarai, T., Girardot, N., St George-Hyslop, P. and Checler, F. 2006. Presenilin-dependent γ-secretase-mediated control of p53-associated cell death in Alzheimer’;s disease. J. Neurosci. 26:6377-6385PubMedCrossRefGoogle Scholar
  3. American Psychiatric Association 2000. Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 4th ed. Washington, DC: American Psychiatric AssociationGoogle Scholar
  4. Anderton, B.H., Betts, J., Blackstock, W.P., Brion, J.P., Chapman, S., Connell, J., Dayanandan, R., Gallo, J.M., Gibb, G., Hanger, D.P., Hutton, M., Kardalinou, E., Leroy, K., Lovestone, S., Mack, T., Reynolds, C.H. and Van Slegtenhorst, M. 2001. Sites of phosphorylation in tau and factors affecting their regulation. Biochem. Soc. Symp. 67:73-80PubMedGoogle Scholar
  5. Ando, Y., Brannstrom, T., Uchida, K., Nyhlin, N., Nasman, B., Suhr, O., Yamashita, T., Olsson, T., El Salhy, M., Uchino, M. and Ando, M. 1998. Histochemical detection of 4-hydroxynonenal protein in Alzheimer amyloid. J. Neurol. Sci. 156:172-176PubMedCrossRefGoogle Scholar
  6. Atamna, H. and Boyle, K. 2006. Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 103:3381-3386PubMedCrossRefGoogle Scholar
  7. Atamna, H. and Frey, W.H., II 2004. A role for heme in Alzheimer’;s disease: Heme binds amyloid β and has altered metabolism. Proc. Natl. Acad. Sci. USA 101:11153-11158PubMedCrossRefGoogle Scholar
  8. Atamna, H., Liu, J. and Ames, B.N. 2001. Heme deficiency selectively interrupts assembly of mitochondrial complex IV in human fibroblasts: Revelance to aging. J. Biol. Chem. 276:48410-48416PubMedGoogle Scholar
  9. Atamna, H., Killilea, D.W., Killilea, A.N. and Ames, B.N. 2002. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl. Acad. Sci. USA 99:14807-14812PubMedCrossRefGoogle Scholar
  10. Banks, W.A. 2004. The source of cerebral insulin. Eur. J. Pharmacol. 490:5-12PubMedCrossRefGoogle Scholar
  11. Barger, S.W. and Mattson, M.P. 1997. Isoform-specific modulation by apolipoprotein E of the activities of secreted β-amyloid precursor protein. J. Neurochem. 69:60-67PubMedCrossRefGoogle Scholar
  12. Baudier, J. and Cole, R.D. 1987. Phosphorylation of tau proteins to a state like that in Alzheimer’;s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J. Biol. Chem. 262:17577-17583PubMedGoogle Scholar
  13. Bayer, K.U., Lohler, J., Schulman, H. and Harbers, K. 1999. Developmental expression of the CaM kinase II isoforms: Ubiquitous γ- and δ-CaM kinase II are the early isoforms and most abundant in the developing nervous system. Brain Res. Mol. Brain Res. 70:147-154PubMedCrossRefGoogle Scholar
  14. Becker, W., Kentrup, H., Klumpp, S., Schultz, J.E. and Joost, H.G. 1994. Molecular cloning of a protein serine/threonine phosphatase containing a putative regulatory tetratricopeptide repeat domain. J. Biol. Chem. 269:22586-22592PubMedGoogle Scholar
  15. Bennecib, M., Gong, C.X., Grundke-Iqbal, I. and Iqbal, K. 2001. Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett. 490:15-22PubMedCrossRefGoogle Scholar
  16. Bennett, B.D., Babu-Khan, S., Loeloff, R., Louis, J.C., Curran, E., Citron, M. and Vassar, R. 2000a. Expression analysis of BACE2 in brain and peripheral tissues. J. Biol. Chem. 275:20647-20651CrossRefGoogle Scholar
  17. Bennett, B.D., Denis, P., Haniu, M., Teplow, D.B., Kahn, S., Louis, J.C., Citron, M. and Vassar, R. 2000b. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’;s β-secretase. J. Biol. Chem. 275:37712-37717CrossRefGoogle Scholar
  18. Berg, M.M., Krafft, G.A. and Klein, W.L. 1997. Rapid impact of β-amyloid on paxillin in a neural cell line. J. Neurosci. Res. 50:979-989PubMedCrossRefGoogle Scholar
  19. Berry, R.W., Abraha, A., Lagalwar, S., La Pointe, N., Gamblin, T.C., Cryns, V.L. and Binder, L.I. 2003. Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. Biochemistry 42:8325-8331PubMedCrossRefGoogle Scholar
  20. Billings, L.M., Oddo, S., Green, K.N., McGaugh, J.L. and La Ferla, F.M. 2005. Intraneuronal Aβ causes the onset of early Alzheimer’;s disease-related cognitive deficits in transgenic mice. Neuron 45:675-688PubMedCrossRefGoogle Scholar
  21. Bitan, G., Kirkitadze, M.D., Lomakin, A., Vollers, S.S., Benedek, G.B. and Teplow, D.B. 2003. Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. USA 100:330-335PubMedCrossRefGoogle Scholar
  22. Blass, J.P., Sheu, K.F., Piacentini, S. and Sorbi, S. 1997. Inherent abnormalities in oxidative metabolism in Alzheimer’;s disease: Interaction with vascular abnormalities. Ann. NY Acad. Sci. 826:382-385PubMedCrossRefGoogle Scholar
  23. Bodles, A.M. and Barger, S.W. 2005. Secreted β-amyloid precursor protein activates microglia via JNK and p38-MAPK. Neurobiol. Aging 26:9-16PubMedCrossRefGoogle Scholar
  24. Boulton, T.G., Nye, S.H., Robbins, D.J., Ip, N.Y., Radziejewska, E., Morgenbesser, S.D., De Pinho, R.A., Panayotatos, N., Cobb, M.H. and Yancopoulos, G.D. 1991. ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65:663-675PubMedCrossRefGoogle Scholar
  25. Braak, H. and Braak, E. 1991. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berlin) 82:239-259CrossRefGoogle Scholar
  26. Braak, H. and Braak, E. 1995. Staging of Alzheimer’;s disease-related neurofibrillary changes. Neurobiol. Aging 16:271-284PubMedCrossRefGoogle Scholar
  27. Brandt, R., Leger, J. and Lee, G. 1995. Interaction of tau with the neural plasma membrane mediated by tau’;s amino-terminal projection domain. J. Cell Biol. 131:1327-1340PubMedCrossRefGoogle Scholar
  28. Braun, A.P. and Schulman, H. 1995. The multifunctional calcium/calmodulin-dependent protein kinase: From form to function. Annu. Rev. Physiol. 57:417-445PubMedCrossRefGoogle Scholar
  29. Breen, A.P. and Murphy, J.A. 1995. Reactions of oxyl radicals with DNA. Free Radic. Biol. Med. 18:1033-1077PubMedCrossRefGoogle Scholar
  30. Buchman, A.S., Wilson, R.S., Bienias, J.L., Shah, R.C., Evans, D.A. and Bennett, D.A. 2005. Change in body mass index and risk of incident Alzheimer disease. Neurology 65:892-897PubMedCrossRefGoogle Scholar
  31. Buee, L., Bussiere, T., Buee-Scherrer, V., Delacourte, A. and Hof, P.R. 2000. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Brain Res. Rev. 33:95-130PubMedCrossRefGoogle Scholar
  32. Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., Yates, J., Cotman, C. and Glabe, C. 1992. Assembly and aggregation properties of synthetic Alzheimer’;s A4/β amyloid peptide analogs. J. Biol. Chem. 267:546-554PubMedGoogle Scholar
  33. Bussiere, T., Giannakopoulos, P., Bouras, C., Perl, D.P., Morrison, J.H. and Hof, P.R. 2003. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer’;s disease: Stereologic analysis of prefrontal cortex area 9. J. Comp. Neurol. 463:281-382PubMedCrossRefGoogle Scholar
  34. Butterfield, D.A. 2002. Amyloid β-peptide(1-42)-induced oxidative stress and neurotoxicity: Implications for neurodegeneration in Alzheimer’;s disease brain. A review. Free Radic. Res. 36:1307-1313CrossRefGoogle Scholar
  35. Butterfield, D.A., Hensley, K., Harris, M., Mattson, M.P. and Carney, J.M. 1994. β-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: Implications to Alzheimer’;s disease. Biochem. Biophys. Res. Commun. 200:710-715PubMedCrossRefGoogle Scholar
  36. Butterfield, D.A., Drake, J., Pocernich, C. and Castegna, A. 2001. Evidence of oxidative damage in Alzheimer’;s disease brain: Central role for amyloid β-peptide. Trends Mol. Med. 7:548-554PubMedCrossRefGoogle Scholar
  37. Butterfield, D.A., Castegna, A., Lauderback, C.M. and Drake, J. 2002a. Evidence that amyloid β-peptide-induced lipid peroxidation and its sequeæ in Alzheimer’;s disease brain contribute to neuronal death. Neurobiol. Aging 23:655-664CrossRefGoogle Scholar
  38. Butterfield, D.A., Griffin, S., Münch, G. and Pasinetti, G.M. 2002b. Amyloid β-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer’;s disease brain exists. J. Alzheimer’;s Dis. 4:193-201Google Scholar
  39. Butterfield, D.A., Perluigi, M. and Sultana, R. 2006. Oxidative stress in Alzheimer’;s disease brain: New insights from redox proteomics. Eur. J. Pharmacol. 545:39-50PubMedCrossRefGoogle Scholar
  40. Butterworth, R.F. and Besnard, A.M. 1990. Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer’;s disease. Metab. Brain Dis. 5:179-184PubMedCrossRefGoogle Scholar
  41. Buxbaum, J.D., Koo, E.H. and Greengard, P. 1993. Protein phosphorylation inhibits production of Alzheimer amyloid β/A4 peptide. Proc. Natl. Acad. Sci. USA 90:9195-9198PubMedCrossRefGoogle Scholar
  42. Campion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., Thomas-Anterion, C., Michon, A., Martin, C., Charbonnier, F., Raux, G., Camuzat, A., Penet, C., Mesnage, V., Martinez, M., Clerget-Darpoux, F., Brice, A. and Frebourg, T. 1999. Early-onset autosomal dominant Alzheimer disease: Prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65:664-670PubMedCrossRefGoogle Scholar
  43. Carlier, M.F., Simon, C., Cassoly, R. and Pradel, L.A. 1984. Interaction between microtubule-associated protein tau and spectrin. Biochimie 66:305-311PubMedCrossRefGoogle Scholar
  44. Carter, J. and Lippa, C.F. 2001. β-amyloid, neuronal death and Alzheimer’;s disease. Curr. Mol. Med. 1:733-737PubMedCrossRefGoogle Scholar
  45. Castellani, R., Smith, M.A., Richey, P.L., Kalaria, R., Gambetti, P. and Perry, G. 1995. Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res. 696:268-271PubMedCrossRefGoogle Scholar
  46. Cervantes, S., Gonzalez-Duarte, R. and Marfany, G. 2001. Homodimerization of presenilin N-terminal fragments is affected by mutations linked to Alzheimer’;s disease. FEBS Lett. 505:81-86PubMedCrossRefGoogle Scholar
  47. Chen, Y.R. and Glabe, C.G. 2006. Distinct early folding and aggregation properties of Alzheimer amyloid-β peptides Aβ40 and Aβ42: Stable trimer or tetramer formation by Aβ42. J. Biol. Chem. 281:24414-24422PubMedCrossRefGoogle Scholar
  48. Chin, S.S. and Goldman, J.E. 1996. Glial inclusions in CNS degenerative diseases. J. Neuropathol. Exp. Neurol. 55:499-508PubMedCrossRefGoogle Scholar
  49. Chyung, J.H., Raper, D.M. and Selkoe, D.J. 2005. γ-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. J. Biol. Chem. 280:4383-4392PubMedCrossRefGoogle Scholar
  50. Coghlan, V.M., Bergeson, S.E., Langeberg, L., Nilaver, G. and Scott, J.D. 1993. A-kinase anchoring proteins: A key to selective activation of cAMP-responsive events? Mol. Cell. Biochem. 127-128:309-319CrossRefGoogle Scholar
  51. Colbran, R.J., Schworer, C.M., Hashimoto, Y., Fong, Y.L., Rich, D.P., Smith, M.K. and Soderling, T.R. 1989. Calcium/calmodulin-dependent protein kinase II. Biochem. J. 258:313-325.PubMedGoogle Scholar
  52. Cook, D.G., Leverenz, J.B., McMillan, P.J., Kulstad, J.J., Ericksen, S., Roth, R.A., Schellenberg, G.D., Jin, L.W., Kovacina, K.S. and Craft, S. 2003. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’;s disease is associated with the apolipoprotein E-ε4allele. Am. J. Pathol. 162:313-319PubMedCrossRefGoogle Scholar
  53. Cooke, M.S., Evans, M.D., Dizdaroglu, M. and Lunec, J. 2003. Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J. 17:1195-1214PubMedCrossRefGoogle Scholar
  54. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’;s disease in late onset families. Science 261:921-923PubMedCrossRefGoogle Scholar
  55. Corder, E.H., Saunders, A.M., Risch, N.J., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Jr., Rimmler, J.B., Locke, P.A., Conneally, P.M., Schmader, K.E., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A. 1994. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7:180-184PubMedCrossRefGoogle Scholar
  56. Correas, I., Padilla, R. and Avila, J. 1990. The tubulin-binding sequence of brain microtubule-associated proteins, tau and MAP-2, is also involved in actin binding. Biochem. J. 269:61-64PubMedGoogle Scholar
  57. Craft, S., Peskind, E., Schwartz, M.W., Schellenberg, G.D., Raskind, M. and Porte, D., Jr. 1998. Cerebrospinal fluid and plasma insulin levels in Alzheimer’;s disease: Relationship to severity of dementia and apolipoprotein E genotype. Neurology 50:164-168PubMedCrossRefGoogle Scholar
  58. Craft, S., Asthana, S., Newcomer, J.W., Wilkinson, C.W., Matos, I.T., Baker, L.D., Cherrier, M., Lofgreen, C., Latendresse, S., Petrova, A., Plymate, S., Raskind, M., Grimwood, K. and Veith, R.C. 1999. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch. Gen. Psychiatry 56:1135-1140PubMedCrossRefGoogle Scholar
  59. Cras, P., Smith, M.A., Richey, P.L., Siedlak, S.L., Mulvihill, P. and Perry, G. 1995. Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathol. (Berlin) 89:291-295CrossRefGoogle Scholar
  60. Creemers, J.W., Ines-Dominguez, D., Plets, E., Serneels, L., Taylor, N.A., Multhaup, G., Craessaerts, K., Annaert, W. and De Strooper, B. 2001. Processing of β-secretase by furin and other members of the proprotein convertase family. J. Biol. Chem. 276:4211-4217PubMedCrossRefGoogle Scholar
  61. Crews, F.T., McElhaney, R., Freund, G., Ballinger, W.E., Jr. and Raizada, M.K. 1992. Insulin-like growth factor I receptor binding in brains of Alzheimer’;s and alcoholic patients. J. Neurochem. 58:1205-1210PubMedCrossRefGoogle Scholar
  62. Crossthwaite, A.J., Hasan, S. and Williams, R.J. 2002. Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: Dependence on Ca2+ and PI3-kinase. J. Neurochem. 80:24-35PubMedCrossRefGoogle Scholar
  63. Cruz, J.C., Tseng, H.C., Goldman, J.A., Shih, H. and Tsai, L.H. 2003. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471-483PubMedCrossRefGoogle Scholar
  64. Cuajungco, M.P. and Faget, K.Y. 2003. Zinc takes the center stage: Its paradoxical role in Alzheimer’;s disease. Brain Res. Brain Res. Rev. 41:44-56PubMedCrossRefGoogle Scholar
  65. Dahlgren, K.N., Manelli, A.M., Stine, W.B., Jr., Baker, L.K., Krafft, G.A. and LaDu, M.J. 2002. Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability. J. Biol. Chem. 277:32046-32053PubMedCrossRefGoogle Scholar
  66. Danbolt, N.C. 2001. Glutamate uptake. Prog. Neurobiol. 65:1-105PubMedCrossRefGoogle Scholar
  67. Demple, B. and Harrison, L. 1994. Repair of oxidative damage to DNA: Enzymology and biology. Annu. Rev. Biochem. 63:915-948PubMedCrossRefGoogle Scholar
  68. D’Ercole, A.J., Ye, P. and O’Kusky, J.R. 2002. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides 36:209-220PubMedCrossRefGoogle Scholar
  69. Derkinderen, P., Enslen, H. and Girault, J.A. 1999. The ERK/MAP-kinases cascade in the nervous system. Neuroreport 10:R24-R34PubMedGoogle Scholar
  70. De Strooper, B., Beullens, M., Contreras, B., Levesque, L., Craessaerts, K., Cordell, B., Moechars, D., Bollen, M., Fraser, P., St George-Hyslop, P. and Van Leuven, F. 1997. Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer’;s disease-associated presenilins. J. Biol. Chem. 272:3590-3598PubMedCrossRefGoogle Scholar
  71. Dhavan, R. and Tsai, L.H. 2001. A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2:749-759PubMedCrossRefGoogle Scholar
  72. Ding, Q., Markesbery, W.R., Chen, Q., Li, F. and Keller, J.N. 2005. Ribosome dysfunction is an early event in Alzheimer’;s disease. J. Neurosci. 25:9171-9175PubMedCrossRefGoogle Scholar
  73. Ditaranto, K., Tekirian, T.L. and Yang, A.J. 2001. Lysosomal membrane damage in soluble Aβ-mediated cell death in Alzheimer’;s disease. Neurobiol. Dis. 8:19-31PubMedCrossRefGoogle Scholar
  74. Dong, D.-L., Xu, Z.-S., Chevrier, M.R., Cotter, R.J., Cleveland, D.W. and Hart, G.W. 1993. Glycosylation of mammalian neurofilaments. Localization of multiple O-linked N-acetylglucosamine moieties on neurofilament polypeptides L and M. J. Biol. Chem. 268:16679-16687PubMedGoogle Scholar
  75. Dore, S., Kar, S. and Quirion, R. 1997. Insulin-like growth factor I protects and rescues hippocampal neurons against β-amyloid- and human amylin-induced toxicity. Proc. Natl. Acad. Sci. USA 94:4772-4777PubMedCrossRefGoogle Scholar
  76. Dore, S., Takahashi, M., Ferris, C.D., Zakhary, R., Hester, L.D., Guastella, D. and Snyder, S.H. 1999. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl. Acad. Sci. USA 96:2445-2450PubMedCrossRefGoogle Scholar
  77. Dorner, A.J., Wasley, L.C. and Kaufman, R.J. 1990. Protein dissociation from GRP78 and secretion are blocked by depletion of cellular ATP levels. Proc. Natl. Acad. Sci. USA 87:7429-7432PubMedCrossRefGoogle Scholar
  78. Drewes, G., Lichtenberg-Kraag, B., Doring, F., Mandelkow, E.M., Biernat, J., Goris, J., Doree, M. and Mandelkow, E. 1992. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 11:2131-2138PubMedGoogle Scholar
  79. Dua, T., Cumbrera, M.G., Mathers, C. and Saxena, S. 2006. Global burden of neurological disorders: Estimates and projections, in Neurological Disorders: Public Health Challenges, eds J.A. Aarli, G. Avanzini, J.M. Bertolote, H. de Boer, H. Breivik, T. Dua, N. Graham, A. Janca J. Kesselring, C. Mathers, A. Muscetta, L. Prilipko, B. Saraceno, S. Saxena T.J. Steiner, pp. 27-40. Geneva, Switzerland: WHO PressGoogle Scholar
  80. Ehehalt, R., Michel, B., De Pietri-Tonelli, D., Zacchetti, D., Simons, K. and Keller, P. 2002. Splice variants of the β-site APP-cleaving enzyme BACE1 in human brain and pancreas. Biochem. Biophys. Res. Commun. 293:30-37PubMedCrossRefGoogle Scholar
  81. Embi, N., Rylatt, D.B. and Cohen, P. 1980. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107:519-527PubMedCrossRefGoogle Scholar
  82. Enslen, H., Raingeaud, J. and Davis, R.J. 1998. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J. Biol. Chem. 273:1741-1748PubMedCrossRefGoogle Scholar
  83. Erecinska, M. and Silver, I.A. 1989. ATP and brain function. J. Cereb. Blood Flow Metab. 9:2-19PubMedCrossRefGoogle Scholar
  84. Esterbauer, H., Schaur, R.J. and Zollner, H. 1991. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 11:81-128PubMedCrossRefGoogle Scholar
  85. Etcheberrigaray, R., Tan, M., Dewachter, I., Kuiperi, C., van der Auwera, I., Wera, S., Qiao, L., Bank, B., Nelson, T.J., Kozikowski, A.P., van Leuven, F. and Alkon, D.L. 2004. Therapeutic effects of PKC activators in Alzheimer’;s disease transgenic mice. Proc. Natl. Acad. Sci. USA 101:11141-11146PubMedCrossRefGoogle Scholar
  86. Ewing, J.F. and Maines, M.D. 1991. Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: Heme oxygenase 2 is not a heat shock protein. Proc. Natl. Acad. Sci. USA 88:5364-5368PubMedCrossRefGoogle Scholar
  87. Farrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., Myers, R.H., Pericak-Vance, M.A., Risch, N. and van Duijn, C.M. 1997. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. J. Am. Med. Assoc. 278:1349-1356CrossRefGoogle Scholar
  88. Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D. and Choe, H. 2000. BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl. Acad. Sci. USA 97:9712-9717PubMedCrossRefGoogle Scholar
  89. Feng, R., Wang, H., Wang, J., Shrom, D., Zeng, X. and Tsien, J.Z. 2004. Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer’;s presenilin-1 and presenilin-2. Proc. Natl. Acad. Sci. USA 101:8162-8167PubMedCrossRefGoogle Scholar
  90. Ferrer, I., Blanco, R., Carmona, M. and Puig, B. 2001a. Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies. J. Neural Transm. 108:1397-1415CrossRefGoogle Scholar
  91. Ferrer, I., Blanco, R., Carmona, M., Ribera, R., Goutan, E., Puig, B., Rey, M.J., Cardozo, A., Vinals, F. and Ribalta, T. 2001b. Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick’;s disease, progressive supranuclear palsy and corticobasal degeneration. Brain Pathol. 11:144-158CrossRefGoogle Scholar
  92. Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang, Y., Jorm, A., Mathers, C., Menezes, P.R., Rimmer, E. and Scazufca, M. 2005. Global prevalence of dementia: A delphi consensus study. Lancet 366:2112-2117PubMedCrossRefGoogle Scholar
  93. Finch, C.E. and Cohen, D.M. 1997. Aging, metabolism, and Alzheimer disease: Review and hypotheses. Exp. Neurol. 143:82-102PubMedCrossRefGoogle Scholar
  94. Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J. and Radulovic, J. 2002. Cyclin-dependent kinase 5 is required for associative learning. J. Neurosci. 22:3700-3707PubMedGoogle Scholar
  95. Fraser, P.E., Yang, D.S., Yu, G., Levesque, L., Nishimura, M., Arawaka, S., Serpell, L.C., Rogaeva, E. and St George-Hyslop, P. 2000. Presenilin structure, function and role in Alzheimer disease. Biochim. Biophys. Acta 1502:1-15PubMedCrossRefGoogle Scholar
  96. Frolich, L., Blum-Degen, D., Bernstein, H.G., Engelsberger, S., Humrich, J., Laufer, S., Muschner, D., Thalheimer, A., Turk, A., Hoyer, S., Zochling, R., Boissl, K.W., Jellinger, K. and Riederer, P. 1998. Brain insulin and insulin receptors in aging and sporadic Alzheimer’;s disease. J. Neural Transm. 105:423-438PubMedCrossRefGoogle Scholar
  97. Frolich, L., Blum-Degen, D., Riederer, P. and Hoyer, S. 1999. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’;s disease. Ann. NY Acad. Sci. 893:290-293PubMedCrossRefGoogle Scholar
  98. Gabbita, S.P., Lovell, M.A. and Markesbery, W.R. 1998. Increased nuclear DNA oxidation in the brain in Alzheimer’;s disease. J. Neurochem. 71:2034-2040PubMedCrossRefGoogle Scholar
  99. Gamblin, T.C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A.L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., Miller, R., Berry, R.W., Binder, L.I. and Cryns, V.L. 2003. Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 100:10032-10037PubMedCrossRefGoogle Scholar
  100. Gasparini, L., Gouras, G.K., Wang, R., Gross, R.S., Beal, M.F., Greengard, P. and Xu, H. 2001. Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling. J. Neurosci. 21:2561-2570PubMedGoogle Scholar
  101. Gasparini, L., Netzer, W.J., Greengard, P. and Xu, H. 2002. Does insulin dysfunction play a role in Alzheimer’;s disease? Trends Pharmacol. Sci. 23:288-293Google Scholar
  102. Gearing, M., Mirra, S.S., Hedreen, J.C., Sumi, S.M., Hansen, L.A. and Heyman, A. 1995. The consortium to establish a registry for Alzheimer’;s disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer’;s disease. Neurology 45:461-466PubMedCrossRefGoogle Scholar
  103. Geula, C., Wu, C.K., Saroff, D., Lorenzo, A., Yuan, M. and Yankner, B.A. 1998. Aging renders the brain vulnerable to amyloid β-protein neurotoxicity. Nat. Med. 4:827-831PubMedCrossRefGoogle Scholar
  104. Ghoshal, N., Smiley, J.F., De Maggio, A.J., Hoekstra, M.F., Cochran, E.J., Binder, L.I. and Kuret, J. 1999. A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer’;s disease. Am. J. Pathol. 155:1163-1172PubMedCrossRefGoogle Scholar
  105. Giancotti, F.G. and Ruoslahti, E. 1999. Integrin signaling. Science 285:1028-1032PubMedCrossRefGoogle Scholar
  106. Giannakopoulos, P., Herrmann, F.R., Bussiere, T., Bouras, C., Kovari, E., Perl, D.P., Morrison, J.H., Gold, G. and Hof, P.R. 2003. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’;s disease. Neurology 60:1495-1500PubMedCrossRefGoogle Scholar
  107. Giasson, B.I., Lee, V.M. and Trojanowski, J.Q. 2003. Interactions of amyloidogenic proteins. Neuromol. Med. 4:49-58CrossRefGoogle Scholar
  108. Giovannone, B., Scaldaferri, M.L., Federici, M., Porzio, O., Lauro, D., Fusco, A., Sbraccia, P., Borboni, P., Lauro, R. and Sesti, G. 2000. Insulin receptor substrate (IRS) transduction system: Distinct and overlapping signaling potential. Diabetes Metab. Res. Rev. 16:434-441PubMedCrossRefGoogle Scholar
  109. Goedert, M., Wischik, C.M., Crowther, R.A., Walker, J.E. and Klug, A. 1988. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85:4051-4055PubMedCrossRefGoogle Scholar
  110. Goedert, M., Spillantini, M.G., Jakes, R., Rutherford, D. and Crowther, R.A. 1989a. Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’;s disease. Neuron 3:519-526CrossRefGoogle Scholar
  111. Goedert, M., Spillantini, M.G., Potier, M.C., Ulrich, J. and Crowther, R.A. 1989b. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: Differential expression of tau protein mRNAs in human brain. EMBO J. 8:393-389Google Scholar
  112. Goedert, M., Cohen, E.S., Jakes, R. and Cohen, P. 1992a. p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer’;s disease [corrected]. FEBS Lett. 312:95-99CrossRefGoogle Scholar
  113. Goedert, M., Spillantini, M.G., Cairns, N.J. and Crowther, R.A. 1992b. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159-168CrossRefGoogle Scholar
  114. Goedert, M., Cuenda, A., Craxton, M., Jakes, R. and Cohen, P. 1997. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 16:3563-3571PubMedCrossRefGoogle Scholar
  115. Gomez-Isla, T., West, H.L., Rebeck, G.W., Harr, S.D., Growdon, J.H., Locascio, J.J., Perls, T.T., Lipsitz, L.A. and Hyman, B.T. 1996. Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer’;s disease. Ann. Neurol. 39:62-70PubMedCrossRefGoogle Scholar
  116. Gomez-Isla, T., Hollister, R., West, H., Mui, S., Growdon, J.H., Petersen, R.C., Parisi, J.E. and Hyman, B.T. 1997. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’;s disease. Ann. Neurol. 41:17-24ssPubMedCrossRefGoogle Scholar
  117. Gomez-Ramos, A., Diaz-Nido, J., Smith, M.A., Perry, G. and Avila, J. 2003. Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J. Neurosci. Res. 71:863-870PubMedCrossRefGoogle Scholar
  118. Gong, C.X., Singh, T.J., Grundke-Iqbal, I. and Iqbal, K. 1993. Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61:921-927PubMedCrossRefGoogle Scholar
  119. Gong, C.X., Grundke-Iqbal, I. and Iqbal, K. 1994a. Dephosphorylation of Alzheimer’;s disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61:765-772CrossRefGoogle Scholar
  120. Gong, C.X., Shaikh, S., Wang, J.Z., Zaidi, T., Grundke-Iqbal, I. and Iqbal, K. 1995. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J. Neurochem. 65:732-738PubMedCrossRefGoogle Scholar
  121. Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I. and Iqbal, K. 2000. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’;s disease. J. Biol. Chem. 275:5535-5544PubMedCrossRefGoogle Scholar
  122. Gong, C.X., Liu, F., Grundke-Iqbal, I. and Iqbal, K. 2005. Post-translational modifications of tau protein in Alzheimer’;s disease. J. Neural Transm. 112:813-838PubMedCrossRefGoogle Scholar
  123. Goodman, Y. and Mattson, M.P. 1994. Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp. Neurol. 128:1-12PubMedCrossRefGoogle Scholar
  124. Goodman, A.B. and Pardee, A.B. 2003. Evidence for defective retinoid transport and function in late onset Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 100:2901-2905PubMedCrossRefGoogle Scholar
  125. Gütz, J., Chen, F., van Dorpe, J. and Nitsch, R.M. 2001. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293:1491-1495CrossRefGoogle Scholar
  126. Gouras, G.K., Tsai, J., Naslund, J., Vincent, B., Edgar, M., Checler, F., Greenfield, J.P., Haroutunian, V., Buxbaum, J.D., Xu, H., Greengard, P. and Relkin, N.R. 2000. Intraneuronal Aβ42 accumulation in human brain. Am. J. Pathol. 156:15-20PubMedCrossRefGoogle Scholar
  127. Grace, E.A. and Busciglio, J. 2003. Aberrant activation of focal adhesion proteins mediates fibrillar amyloid β-induced neuronal dystrophy. J. Neurosci. 23:493-502PubMedGoogle Scholar
  128. Griffith, L.M. and Pollard, T.D. 1982. The interaction of actin filaments with microtubules and microtubule-associated proteins. J. Biol. Chem. 257:9143-9151PubMedGoogle Scholar
  129. Griffith, L.S., Mathes, M. and Schmitz, B. 1995. β-amyloid precursor protein is modified with O-linked N-acetylglucosamine. J. Neurosci. Res. 41:270-278PubMedCrossRefGoogle Scholar
  130. Growdon, J.H., Locascio, J.J., Corkin, S., Gomez-Isla, T. and Hyman, B.T. 1996. Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer’;s disease. Neurology 47:444-448PubMedCrossRefGoogle Scholar
  131. Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y.C., Zaidi, M.S. and Wisniewski, H.M. 1986a. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261:6084-6089Google Scholar
  132. Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M. and Binder, L.I. 1986b. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83:4913-4917CrossRefGoogle Scholar
  133. Guillemin, G.J., Williams, K.R., Smith, D.G., Smythe, G.A., Croitoru-Lamoury, J. and Brew, B.J. 2003. Quinolinic acid in the pathogenesis of Alzheimer’;s disease. Adv. Exp. Med. Biol. 527:167-176PubMedCrossRefGoogle Scholar
  134. Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard, B. and Davis, R.J. 1996. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15:2760-2770PubMedGoogle Scholar
  135. Gurland, B.J., Wilder, D.E., Lantigua, R., Stern, Y., Chen, J., Killeffer, E.H. and Mayeux, R. 1999. Rates of dementia in three ethnoracial groups. Int. J. Geriat. Psychiatry 14:481-493CrossRefGoogle Scholar
  136. Haass, C. and Steiner, H. 2001. Protofibrils, the unifying toxic molecule of neurodegenerative disorders? Nat. Neurosci. 4:859-860Google Scholar
  137. Haass, C., Lemere, C.A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L. and Selkoe, D.J. 1995. The Swedish mutation causes early-onset Alzheimer’;s disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1:1291-1296PubMedCrossRefGoogle Scholar
  138. Hanger, D.P., Betts, J.C., Loviny, T.L., Blackstock, W.P. and Anderton, B.H. 1998. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’;s disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71:2465-2476PubMedCrossRefGoogle Scholar
  139. Hansen, L.A., Masliah, E., Galasko, D. and Terry, R.D. 1993. Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa. J. Neuropathol. Exp. Neurol. 52:648-654PubMedCrossRefGoogle Scholar
  140. Harada, H., Tamaoka, A., Ishii, K., Shoji, S., Kametaka, S., Kametani, F., Saito, Y. and Murayama, S. 2006. β-Site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer’;s disease brains. Neurosci. Res. 54:24-29PubMedCrossRefGoogle Scholar
  141. Hardy, J.A. and Selkoe, D.J. 2002. The amyloid hypothesis of Alzheimer’;s disease: Progress and problems on the road to therapeutics. Science 297:353-356PubMedCrossRefGoogle Scholar
  142. Harris, M.E., Wang, Y., Pedigo, N.W., Jr., Hensley, K., Butterfield, D.A. and Carney, J.M. 1996. Amyloid β peptide (25-35) inhibits Na-dependent glutamate uptake in rat hippocampal astrocyte cultures. J. Neurochem. 67:277-286PubMedCrossRefGoogle Scholar
  143. Harris, F.M., Tesseur, I., Brecht, W.J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R.W. and Huang, Y. 2004. Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer’;s disease. J. Biol. Chem. 279:3862-3868PubMedCrossRefGoogle Scholar
  144. Hart, G.W. 1997. Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu. Rev. Biochem. 66:315-335PubMedCrossRefGoogle Scholar
  145. Hasegawa, M., Jakes, R., Crowther, R.A., Lee, V.M., Ihara, Y. and Goedert, M. 1996. Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. FEBS Lett. 384:25-30PubMedCrossRefGoogle Scholar
  146. Hata, R., Masumura, M., Akatsu, H., Li, F., Fujita, H., Nagai, Y., Yamamoto, T., Okada, H., Kosaka, K., Sakanaka, M. and Sawada, T. 2001. Up-regulation of calcineurin Aβ mRNA in the Alzheimer’;s disease brain: Assessment by cDNA microarray. Biochem. Biophys. Res. Commun. 284:310-316PubMedCrossRefGoogle Scholar
  147. Hayakawa, H. and Sekiguchi, M. 2006. Human polynucleotide phosphorylase protein in response to oxidative stress. Biochemistry 45:6749-6755PubMedCrossRefGoogle Scholar
  148. Hayakawa, H., Uchiumi, T., Fukuda, T., Ashizuka, M., Kohno, K., Kuwano, M. and Sekiguchi, M. 2002. Binding capacity of human YB-1 protein for RNA containing 8-oxoguanine. Biochemistry 41:12739-12744PubMedCrossRefGoogle Scholar
  149. Hensley, K., Floyd, R.A., Zheng, N.Y., Nael, R., Robinson, K.A., Nguyen, X., Pye, Q.N., Stewart, C.A., Geddes, J., Markesbery, W.R., Patel, E., Johnson, G.V. and Bing, G. 1999. p38 kinase is activated in the Alzheimer’;s disease brain. J. Neurochem. 72:2053-2058PubMedCrossRefGoogle Scholar
  150. Herzig, S. and Neumann, J. 2000. Effects of serine/threonine protein phosphatases on ion channels in excitable membranes. Physiol. Rev. 80:173-210PubMedGoogle Scholar
  151. Himmler, A., Drechsel, D., Kirschner, M.W. and Martin, D.W., Jr. 1989. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell. Biol. 9:1381-1388PubMedGoogle Scholar
  152. Hisanaga, S. and Saito, T. 2003. The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals 12:221-229PubMedCrossRefGoogle Scholar
  153. Hof, P.R., Delacourte, A. and Bouras, C. 1992. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: A quantitative analysis of six cases. Acta Neuropathol. (Berlin) 84:45-51CrossRefGoogle Scholar
  154. Hof, P.R., Bouras, C., Perl, D.P. and Morrison, J.H. 1994. Quantitative neuropathologic analysis of Pick’;s disease cases: Cortical distribution of Pick bodies and coexistence with Alzheimer’;s disease. Acta Neuropathol. (Berlin) 87:115-124CrossRefGoogle Scholar
  155. Hoglund, K., Thelen, K.M., Syversen, S., Sjogren, M., von Bergmann, K., Wallin, A., Vanmechelen, E., Vanderstichele, H., Lutjohann, D. and Blennow, K. 2005. The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer’;s disease. Dement. Geriatr. Cogn. Disord. 19:256-265PubMedCrossRefGoogle Scholar
  156. Holtzman, D.M., Bales, K.R., Tenkova, T., Fagan, A.M., Parsadanian, M., Sartorius, L.J., Mackey, B., Olney, J., McKeel, D., Wozniak, D. and Paul, S.M. 2000. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 97:2892-2897PubMedCrossRefGoogle Scholar
  157. Hong, M. and Lee, V.M. 1997. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J. Biol. Chem. 272:19547-19553PubMedCrossRefGoogle Scholar
  158. Howlett, D., Cutler, P., Heales, S. and Camilleri, P. 1997. Hemin and related porphyrins inhibit β-amyloid aggregation. FEBS Lett. 417:249-251PubMedCrossRefGoogle Scholar
  159. Hoyer, S. 1992. Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases. Mol. Chem. Neuropathol. 16:207-224PubMedCrossRefGoogle Scholar
  160. Hoyer, S. 2000. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: An update. Exp. Gerontol. 35:1363-1372CrossRefGoogle Scholar
  161. Huang, Y., Weisgraber, K.H., Mucke, L. and Mahley, R.W. 2004. Apolipoprotein E: Diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’;s disease. J. Mol. Neurosci. 23:189-204PubMedCrossRefGoogle Scholar
  162. Huse, J.T., Pijak, D.S., Leslie, G.J., Lee, V.M. and Doms, R.W. 2000. Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme. The Alzheimer’;s disease β-secretase. J. Biol. Chem. 275:33729-33737PubMedCrossRefGoogle Scholar
  163. Hwang, S.C., Jhon, D.Y., Bae, Y.S., Kim, J.H. and Rhee, S.G. 1996. Activation of phospholipase Cγ by the concerted action of tau proteins and arachidonic acid. J. Biol. Chem. 271:18342-18349PubMedCrossRefGoogle Scholar
  164. Hyman, B.T., Elvhage, T.E. and Reiter, J. 1994. Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer’;s disease. Am. J. Pathol. 144:565-572PubMedGoogle Scholar
  165. Hyman, B.T., Gomez-Isla, T., Rebeck, G.W., Briggs, M., Chung, H., West, H.L., Greenberg, S., Mui, S., Nichols, S., Wallace, R. and Growdon, J.H. 1996a. Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer’;s disease. Ann. NY Acad. Sci. 802:1-5CrossRefGoogle Scholar
  166. Hyman, B.T., Gomez-Isla, T., West, H., Briggs, M., Chung, H., Growdon, J.H. and Rebeck, G.W. 1996b. Clinical and neuropathological correlates of apolipoprotein E genotype in Alzheimer’;s disease. Window on molecular epidemiology. Ann. NY Acad. Sci. 777:158-165CrossRefGoogle Scholar
  167. Hynd, M.R., Scott, H.L. and Dodd, P.R. 2004. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’;s disease. Neurochem. Int. 45:583-595PubMedCrossRefGoogle Scholar
  168. Iijima, K., Ando, K., Takeda, S., Satoh, Y., Seki, T., Itohara, S., Greengard, P., Kirino, Y., Nairn, A.C. and Suzuki, T. 2000. Neuron-specific phosphorylation of Alzheimer’;s β-amyloid precursor protein by cyclin-dependent kinase 5. J. Neurochem. 75:1085-1091PubMedCrossRefGoogle Scholar
  169. Ikeda, K., Urakami, K., Isoe, K., Ohno, K. and Nakashima, K. 1998. The expression of presenilin-1 mRNA in skin fibroblasts from Alzheimer’;s disease. Dement. Geriatr. Cogn. Disord. 9:145-148PubMedCrossRefGoogle Scholar
  170. Ingelson, M., Vanmechelen, E. and Lannfelt, L. 1996. Microtubule-associated protein tau in human fibroblasts with the Swedish Alzheimer mutation. Neurosci. Lett. 220:9-12PubMedCrossRefGoogle Scholar
  171. Intebi, A.D., Garau, L., Brusco, I., Pagano, M., Gaillard, R.C. and Spinedi, E. 2002. Alzheimer’;s disease patients display gender dimorphism in circulating anorectic adipokines. Neuroimmunomodulation 10:351-358PubMedCrossRefGoogle Scholar
  172. Iqbal, K., Grundke-Iqbal, I., Zaidi, T., Merz, P.A., Wen, G.Y., Shaikh, S.S., Wisniewski, H.M., Alafuzoff, I. and Winblad, B. 1986. Defective brain microtubule assembly in Alzheimer’;s disease. Lancet 2:421-426PubMedCrossRefGoogle Scholar
  173. Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M.O., El-Akkad, E., Gong, C.X., Khatoon, S., Li, B., Liu, F., Rahman, A., Tanimukai, H. and Grundke-Iqbal, I. 2005. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739:198-210PubMedCrossRefGoogle Scholar
  174. Ishibashi, T., Hayakawa, H., Ito, R., Miyazawa, M., Yamagata, Y. and Sekiguchi, M. 2005. Mammalian enzymes for preventing transcriptional errors caused by oxidative damage. Nucleic Acids Res. 33:3779-3784PubMedCrossRefGoogle Scholar
  175. Ishii, K., Tamaoka, A., Mizusawa, H., Shoji, S., Ohtake, T., Fraser, P.E., Takahashi, H., Tsuji, S., Gearing, M., Mizutani, T., Yamada, S., Kato, M., St George-Hyslop, P.H., Mirra, S.S. and Mori, H. 1997. Aβ1-40 but not Aβ1-42 levels in cortex correlate with apolipoprotein E ε4 allele dosage in sporadic Alzheimer’;s disease. Brain Res. 748:250-252PubMedCrossRefGoogle Scholar
  176. Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N. and Ihara, Y. 1994. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43). Neuron 13:45-53PubMedCrossRefGoogle Scholar
  177. Jafferali, S., Dumont, Y., Sotty, F., Robitaille, Y., Quirion, R. and Kar, S. 2000. Insulin-like growth factor-I and its receptor in the frontal cortex, hippocampus, and cerebellum of normal human and Alzheimer disease brains. Synapse 38:450-459PubMedCrossRefGoogle Scholar
  178. Jagust, W.J., Seab, J.P., Huesman, R.H., Valk, P.E., Mathis, C.A., Reed, B.R., Coxson, P.G. and Budinger, T.F. 1991. Diminished glucose transport in Alzheimer’;s disease: Dynamic PET studies. J. Cereb. Blood Flow Metab. 11:323-330PubMedCrossRefGoogle Scholar
  179. Jarrett, J.T., Berger, E.P. and Lansbury, P.T., Jr. 1993. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer’;s disease. Biochemistry 32:4693-4697PubMedCrossRefGoogle Scholar
  180. Ji, Z.-S., Miranda, R.D., Newhouse, Y.M., Weisgraber, K.H., Huang, Y. and Mahley, R.W. 2002. Apolipoprotein E4 potentiates amyloid β peptide-induced lysosomal leakage and apoptosis in neuronal cells. J. Biol. Chem. 277:21821-21828PubMedCrossRefGoogle Scholar
  181. Ji, Z.-S., Mullendorff, K., Cheng, I.-H., Miranda, R.D., Huang, Y. and Mahley, R.W. 2006. Reactivity of apolipoprotein E4 and amyloid β peptide: Lysosomal stability and neurodegeneration. J. Biol. Chem. 281:2683-2692PubMedCrossRefGoogle Scholar
  182. Jicha, G.A., Weaver, C., Lane, E., Vianna, C., Kress, Y., Rockwood, J. and Davies, P. 1999. cAMP-dependent protein kinase phosphorylations on tau in Alzheimer’;s disease. J. Neurosci. 19:7486-7494PubMedGoogle Scholar
  183. Johnson, G.V. and Hartigan, J.A. 1999. Tau protein in normal and Alzheimer’;s disease brain: An update. J. Alzheimer’;s Dis. 1:329-351Google Scholar
  184. Jonker, C., Schmand, B., Lindeboom, J., Havekes, L.M. and Launer, L.J. 1998. Association between apolipoprotein E ε4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Arch. Neurol. 55:1065-1069PubMedCrossRefGoogle Scholar
  185. Jonsson, L., Eriksdotter-Jonhagen, M., Kilander, L., Soininen, H., Hallikainen, M., Waldemar, G., Nygaard, H., Andreasen, N., Winblad, B. and Wimo, A. 2006. Determinants of costs of care for patients with Alzheimer’;s disease. Int. J. Geriatr. Psychiatry 21:449-459PubMedCrossRefGoogle Scholar
  186. Kaether, C. and Haass, C. 2004. A lipid boundary separates APP and secretases and limits amyloid β-peptide generation. J. Cell Biol. 167:809-812PubMedCrossRefGoogle Scholar
  187. Kamal, A., Stokin, G.B., Yang, Z., Xia, C.H. and Goldstein, L.S. 2000. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28:449-459PubMedCrossRefGoogle Scholar
  188. Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuther, K. and Mller-Hill, B. 1987. The precursor of Alzheimer’;s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733-736PubMedCrossRefGoogle Scholar
  189. Kannanayakal, T.J., Tao, H., Vandre, D.D. and Kuret, J. 2006. Casein kinase-1 isoforms differentially associate with neurofibrillary and granulovacuolar degeneration lesions. Acta Neuropathol. (Berlin) 111:413-421CrossRefGoogle Scholar
  190. Katzman, R. 1986. Alzheimer’;s disease. N. Engl. J. Med. 314:964-973PubMedCrossRefGoogle Scholar
  191. Kaufman, R.J. 1999. Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls. Genes Dev. 13:1211-1233PubMedCrossRefGoogle Scholar
  192. Keller, J.N., Mark, R.J., Bruce, A.J., Blanc, E., Rothstein, J.D., Uchida, K., Waeg, G. and Mattson, M.P. 1997a. 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80:685-696CrossRefGoogle Scholar
  193. Keller, J.N., Pang, Z., Geddes, J.W., Begley, J.G., Germeyer, A., Waeg, G. and Mattson, M.P. 1997b. Impairment 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-hydroxynonenal. J. Neurochem. 69:273-284CrossRefGoogle Scholar
  194. Kelly, P.T., McGuinness, T.L. and Greengard, P. 1984. Evidence that the major postsynaptic density protein is a component of a Ca2+/calmodulin-dependent protein kinase. Proc. Natl. Acad. Sci. USA. 81:945-949PubMedCrossRefGoogle Scholar
  195. Killilea, D.W., Atamna, H., Liao, C. and Ames, B.N. 2003. Iron accumulation during cellular senescence in human fibroblasts in vitro. Antioxid. Redox Signal. 5:507-516PubMedCrossRefGoogle Scholar
  196. Kimpara, T., Takeda, A., Yamaguchi, T., Arai, H., Okita, N., Takase, S., Sasaki, H. and Itoyama, Y. 2000. Increased bilirubins and their derivatives in cerebrospinal fluid in Alzheimer’;s disease. Neurobiol. Aging 21:551-554PubMedCrossRefGoogle Scholar
  197. King, G.L. and Johnson, S.M. 1985. Receptor-mediated transport of insulin across endothelial cells. Science 227:1583-1586PubMedCrossRefGoogle Scholar
  198. Kins, S., Kurosinski, P., Nitsch, R.M. and Gotz, J. 2003. Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice. Am. J. Pathol. 163:833-843PubMedCrossRefGoogle Scholar
  199. Kirkitadze, M.D., Condron, M.M. and Teplow, D.B. 2001. Identification and characterization of key kinetic intermediates in amyloid β-protein fibrillogenesis. J. Mol. Biol. 312:1103-1119PubMedCrossRefGoogle Scholar
  200. Knippschild, U., Gocht, A., Wolff, S., Huber, N., Lohler, J. and Stoter, M. 2005. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 17:675-689PubMedCrossRefGoogle Scholar
  201. Knopman, D.S., DeKosky, S.T., Cummings, J.L., Chui, H., Corey-Bloom, J., Relkin, N., Small, G.W., Miller, B. and Stevens, J.C. 2001. Practice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1143-1153PubMedCrossRefGoogle Scholar
  202. Kojro, E., Gimpl, G., Lammich, S., Marz, W. and Fahrenholz, F. 2001. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc. Natl. Acad. Sci. USA. 98:5815-5820PubMedCrossRefGoogle Scholar
  203. Kojro, E., Postina, R., Buro, C., Meiringer, C., Gehrig-Burger, K. and Fahrenholz, F. 2006. The neuropeptide PACAP promotes the α-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J. 20:512-514PubMedGoogle Scholar
  204. Kopke, E., Tung, Y.C., Shaikh, S., Alonso, A.C., Iqbal, K. and Grundke-Iqbal, I. 1993. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268:24374-24384PubMedGoogle Scholar
  205. Kumar, S., McDonnell, P.C., Gum, R.J., Hand, A.T., Lee, J.C. and Young, P.R. 1997. Novel homologues of CSBP/p38 MAP kinase: Activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem. Biophys. Res. Commun. 235:533-538PubMedCrossRefGoogle Scholar
  206. Kusakawa, G., Saito, T., Onuki, R., Ishiguro, K., Kishimoto, T. and Hisanaga, S. 2000. Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. J. Biol. Chem. 275:17166-17172PubMedCrossRefGoogle Scholar
  207. La Du, M.J., Falduto, M.T., Manelli, A.M., Reardon, C.A., Getz, G.S. and Frail, D.E. 1994. Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269:23403-23406Google Scholar
  208. La Ferla, F.M., Tinkle, B.T., Bieberich, C.J., Haudenschild, C.C. and Jay, G. 1995. The Alzheimer’;s Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat. Genet. 9:21-30CrossRefGoogle Scholar
  209. Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C. and Fahrenholz, F. 1999. Constitutive and regulated α-secretase cleavage of Alzheimer’;s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA. 96:3922-3927PubMedCrossRefGoogle Scholar
  210. Lauderback, C.M., Hackett, J.M., Huang, F.F., Keller, J.N., Szweda, L.I., Markesbery, W.R. and Butterfield, D.A. 2001. The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’;s disease brain: The role of Aβ<Subscript>1-42</Subscript>. J. Neurochem. 78:413-416PubMedCrossRefGoogle Scholar
  211. Lee, G., Newman, S.T., Gard, D.L., Band, H. and Panchamoorthy, G. 1998. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 111:3167-3177PubMedGoogle Scholar
  212. Lee, V.M., Goedert, M. and Trojanowski, J.Q. 2001. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24:1121-1159PubMedCrossRefGoogle Scholar
  213. Lee, C.W., Lau, K.F., Miller, C.C. and Shaw, P.C. 2003a. Glycogen synthase kinase-3 β-mediated tau phosphorylation in cultured cell lines. Neuroreport 14:257-260CrossRefGoogle Scholar
  214. Lee, M.S., Kao, S.C., Lemere, C.A., Xia, W., Tseng, H.C., Zhou, Y., Neve, R., Ahlijanian, M.K. and Tsai, L.H. 2003b. APP processing is regulated by cytoplasmic phosphorylation. J. Cell Biol. 163:83-95CrossRefGoogle Scholar
  215. Leissring, M.A., Farris, W., Chang, A.Y., Walsh, D.M., Wu, X., Sun, X., Frosch, M.P. and Selkoe, D.J. 2003. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40:1087-1093PubMedCrossRefGoogle Scholar
  216. Lemere, C.A., Lopera, F., Kosik, K.S., Lendon, C.L., Ossa, J., Saido, T.C., Yamaguchi, H., Ruiz, A., Martinez, A., Madrigal, L., Hincapie, L., Arango, J.C., Anthony, D.C., Koo, E.H., Goate, A.M. and Selkoe, D.J. 1996. The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat. Med. 2:1146-1150PubMedCrossRefGoogle Scholar
  217. Lew, J., Huang, Q.Q., Qi, Z., Winkfein, R.J., Aebersold, R., Hunt, T. and Wang, J.H. 1994. A brain-specific activator of cyclin-dependent kinase 5. Nature 371:423-426PubMedCrossRefGoogle Scholar
  218. Li, M., Guo, H. and Damuni, Z. 1995. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry 34:1988-1996PubMedCrossRefGoogle Scholar
  219. Li, Z., Jiang, Y., Ulevitch, R.J. and Han, J. 1996a. The primary structure of p38γ: A new member of p38 group of MAP kinases. Biochem. Biophys. Res. Commun. 228:334-340CrossRefGoogle Scholar
  220. Li, M., Makkinje, A. and Damuni, Z. 1996b. Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 35:6998CrossRefGoogle Scholar
  221. Li, R., Lindholm, K., Yang, L.B., Yue, X., Citron, M., Yan, R., Beach, T., Sue, L., Sabbagh, M., Cai, H., Wong, P., Price, D. and Shen, Y. 2004a. Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer’;s disease patients. Proc. Natl. Acad. Sci. USA. 101:3632-3637CrossRefGoogle Scholar
  222. Li, Z., Okamoto, K., Hayashi, Y. and Sheng, M. 2004b. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873-887CrossRefGoogle Scholar
  223. Li, G., Yin, H. and Kuret, J. 2004c. Casein kinase 1δ phosphorylates tau and disrupts its binding to microtubules. J. Biol. Chem. 279:15938-15945CrossRefGoogle Scholar
  224. Lian, Q., Ladner, C.J., Magnuson, D. and Lee, J.M. 2001. Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer’;s disease cerebral cortex. Exp. Neurol. 167:158-165PubMedCrossRefGoogle Scholar
  225. Ling, X., Martins, R.N., Racchi, M., Craft, S. and Helmerhorst, E. 2002. Amyloid β antagonizes insulin promoted secretion of the amyloid β protein precursor. J. Alzheimer’;s Dis. 4:369-374Google Scholar
  226. Lippa, C.F., Schmidt, M.L., Nee, L.E., Bird, T., Nochlin, D., Hulette, C., Mori, H., Lee, V.M. and Trojanowski, J.Q. 2000. AMY plaques in familial AD: Comparison with sporadic Alzheimer’;s disease. Neurology 54:100-104PubMedCrossRefGoogle Scholar
  227. Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G.W. and Gong, C.-X. 2004a. O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 101:10804-10809CrossRefGoogle Scholar
  228. Liu, S.-J., Zhang, J.-Y., Li, H.-L., Fang, Z.-Y., Wang, Q., Deng, H.-M., Gong, C.-X., Grundke-Iqbal, I., Iqbal, K. and Wang, J.-Z. 2004b. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J. Biol. Chem. 279:50078-50088CrossRefGoogle Scholar
  229. Liu, F., Grundke-Iqbal, I., Iqbal, K. and Gong, C.X. 2005a. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22:1942-1950CrossRefGoogle Scholar
  230. Liu, F., Iqbal, K., Grundke-Iqbal, I., Rossie, S. and Gong, C.X. 2005b. Dephosphorylation of tau by protein phosphatase 5: Impairment in Alzheimer’;s disease. J. Biol. Chem. 280:1790-1796CrossRefGoogle Scholar
  231. Liu, G.-P., Zhang, Y., Yao, X.-Q., Zhang, C.-E., Fang, J., Wang, Q. and Wang, J.-Z. 2007. Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiol. AgingGoogle Scholar
  232. Lovell, M.A., Xie, C. and Markesbery, W.R. 2000. Decreased base excision repair and increased helicase activity in Alzheimer’;s disease brain. Brain Res. 855:116-123PubMedCrossRefGoogle Scholar
  233. Lovestone, S. and Reynolds, C.H. 1997. The phosphorylation of tau: A critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 78:309-324PubMedCrossRefGoogle Scholar
  234. Lovestone, S., Anderton, B.H., Hartley, C., Jensen, T.G. and Jorgensen, A.L. 1996. The intracellular fate of apolipoprotein E is tau dependent and APOE allele-specific. Neuroreport 7:1005-1008PubMedCrossRefGoogle Scholar
  235. Lu, Q., Soria, J.P. and Wood, J.G. 1993. p44mpk MAP kinase induces Alzheimer type alterations in tau function and in primary hippocampal neurons. J. Neurosci. Res. 35:439-444PubMedCrossRefGoogle Scholar
  236. Lue, L.F., Kuo, Y.M., Roher, A.E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J.H., Rydel, R.E. and Rogers, J. 1999. Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer’;s disease. Am. J. Pathol. 155:853-862PubMedCrossRefGoogle Scholar
  237. Madl, J.E. and Burgesser, K. 1993. Adenosine triphosphate depletion reverses sodium-dependent, neuronal uptake of glutamate in rat hippocampal slices. J. Neurosci. 13:4429-4444PubMedGoogle Scholar
  238. Mahley, R.W. 1988. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240:622-630PubMedCrossRefGoogle Scholar
  239. Mahley, R.W. and Huang, Y. 2006. Apolipoprotein (apo) E4 and Alzheimer’;s disease: Unique conformational and biophysical properties of apoE4 can modulate neuropathology. Acta Neurol. Scand. Suppl. 185:8-14PubMedCrossRefGoogle Scholar
  240. Mahley, R.W. and Rall, S.C., Jr. 2000. Apolipoprotein E: Far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1:507-537PubMedCrossRefGoogle Scholar
  241. Mahley, R.W., Weisgraber, K.H. and Huang, Y.-D. 2006. Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 103:5644-5651PubMedCrossRefGoogle Scholar
  242. Mandelkow, E.M., Drewes, G., Biernat, J., Gustke, N., van Lint, J., Vandenheede, J.R. and Mandelkow, E. 1992. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314:315-321PubMedCrossRefGoogle Scholar
  243. Mark, R.J., Lovell, M.A., Markesbery, W.R., Uchida, K. and Mattson, M.P. 1997a. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J. Neurochem. 68:255-264CrossRefGoogle Scholar
  244. Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K. and Mattson, M.P. 1997b. Amyloid β-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17:1046-1054Google Scholar
  245. Markesbery, W.R. and Lovell, M.A. 1998. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’;s disease. Neurobiol. Aging 19:33-36PubMedCrossRefGoogle Scholar
  246. Marquez-Sterling, N.R., Lo, A.C., Sisodia, S.S. and Koo, E.H. 1997. Trafficking of cell-surface β-amyloid precursor protein: Evidence that a sorting intermediate participates in synaptic vesicle recycling. J. Neurosci. 17:140-151PubMedGoogle Scholar
  247. Marshall, S., Nadeau, O. and Yamasaki, K. 2004. Dynamic actions of glucose and glucosamine on hexosamine biosynthesis in isolated adipocytes: Differential effects on glucosamine 6-phosphate, UDP-N-acetylglucosamine, and ATP levels. J. Biol. Chem. 279:35313-35319PubMedCrossRefGoogle Scholar
  248. Mastrogiacomo, F., Bergeron, C. and Kish, S.J. 1993. Brain α-ketoglutarate dehydrogenase complex activity in Alzheimer’;s disease. J. Neurochem. 61:2007-2014PubMedCrossRefGoogle Scholar
  249. Matsuo, E.S., Shin, R.W., Billingsley, M.L., Van deVoorde, A., OConnor, M., Trojanowski, J.Q. and Lee, V.M. 1994. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’;s disease paired helical filament tau. Neuron 13:989-1002PubMedCrossRefGoogle Scholar
  250. McDermott, J.R. and Gibson, A.M. 1997. Degradation of Alzheimer’;s β-amyloid protein by human and rat brain peptidases: Involvement of insulin-degrading enzyme. Neurochem. Res. 22:49-56PubMedCrossRefGoogle Scholar
  251. McEwen, B.S. and Reagan, L.P. 2004. Glucose transporter expression in the central nervous system: Relationship to synaptic function. Eur. J. Pharmacol. 490:13-24PubMedCrossRefGoogle Scholar
  252. McKee, A.C., Kosik, K.S., Kennedy, M.B. and Kowall, N.W. 1990. Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase. J. Neuropathol. Exp. Neurol. 49:49-63PubMedCrossRefGoogle Scholar
  253. McLean, C.A., Cherny, R.A., Fraser, F.W., Fuller, S.J., Smith, M.J., Beyreuther, K., Bush, A.I. and Masters, C.L. 1999. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’;s disease. Ann. Neurol. 46:860-866PubMedCrossRefGoogle Scholar
  254. McMillan, P.J., Leverenz, J.B. and Dorsa, D.M. 2000. Specific downregulation of presenilin 2 gene expression is prominent during early stages of sporadic late-onset Alzheimer’;s disease. Brain Res. Mol. Brain Res. 78:138-145PubMedCrossRefGoogle Scholar
  255. McShea, A., Zelasko, D.A., Gerst, J.L. and Smith, M.A. 1999. Signal transduction abnormalities in Alzheimer’;s disease: Evidence of a pathogenic stimuli. Brain Res. 815:237-242PubMedCrossRefGoogle Scholar
  256. Mercken, M., Vandermeeren, M., Lubke, U., Six, J., Boons, J., van de Voorde, A., Martin, J.J. and Gheuens, J. 1992. Monoclonal antibodies with selective specificity for Alzheimer tau are directed against phosphatase-sensitive epitopes. Acta Neuropathol. (Berlin) 84:265-272CrossRefGoogle Scholar
  257. Michikawa, M. and Yanagisawa, K. 1999. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J. Neurochem. 72:2278-2285PubMedCrossRefGoogle Scholar
  258. Misonou, H., Morishima-Kawashima, M. and Ihara, Y. 2000. Oxidative stress induces intracellular accumulation of amyloid β-protein (Aβ) in human neuroblastoma cells. Biochemistry 39:6951-6959PubMedCrossRefGoogle Scholar
  259. Mooradian, A.D., Chung, H.-C. and Shah, G.N. 1997. GLUT-1 expression in the cerebra of patients with Alzheimer’;s disease. Neurobiol. Aging 18:469-474PubMedCrossRefGoogle Scholar
  260. Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Watanabe, A., Titani, K. and Ihara, Y. 1995. Hyperphosphorylation of tau in PHF. Neurobiol. Aging 16:365-371PubMedCrossRefGoogle Scholar
  261. Mullaart, E., Boerrigter, M.E., Ravid, R., Swaab, D.F. and Vijg, J. 1990. Increased levels of DNA breaks in cerebral cortex of Alzheimer’;s disease patients. Neurobiol. Aging 11:169-173PubMedCrossRefGoogle Scholar
  262. Nakabeppu, Y., Kajitani, K., Sakamoto, K., Yamaguchi, H. and Tsuchimoto, D. 2006. MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. DNA Repair 5:761-772PubMedCrossRefGoogle Scholar
  263. Nathan, B.P., Bellosta, S., Sanan, D.A., Weisgraber, K.H., Mahley, R.W. and Pitas, R.E. 1994. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264:850-852PubMedCrossRefGoogle Scholar
  264. Nelson, P.T., Stefansson, K., Gulcher, J. and Saper, C.B. 1996. Molecular evolution of tau protein: Implications for Alzheimer’;s disease. J. Neurochem. 67:1622-1632PubMedCrossRefGoogle Scholar
  265. Nicholls, D. and Attwell, D. 1990. The release and uptake of excitatory amino acids. Trends Pharmacol. Sci. 11:462-468PubMedCrossRefGoogle Scholar
  266. Noble, W., Olm, V., Takata, K., Casey, E., Mary, O., Meyerson, J., Gaynor, K., LaFrancois, J., Wang, L., Kondo, T., Davies, P., Burns, M., Veeranna, Nixon, R., Dickson, D., Matsuoka, Y., Ahlijanian, M., Lau, L.F. and Duff, K. 2003. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555-565PubMedCrossRefGoogle Scholar
  267. Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E.K., Jones, P.K., Ghanbari, H., Wataya, T., Shimohama, S., Chiba, S., Atwood, C.S., Petersen, R.B. and Smith, M.A. 2001. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60:759-767PubMedGoogle Scholar
  268. Nunomura, A., Chiba, S., Lippa, C.F., Cras, P., Kalaria, R.N., Takeda, A., Honda, K., Smith, M.A. and Perry, G. 2004. Neuronal RNA oxidation is a prominent feature of familial Alzheimer’;s disease. Neurobiol. Dis. 17:108-113PubMedCrossRefGoogle Scholar
  269. O’Kusky, J.R., Ye, P. and D’Ercole, A.J. 2000. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J. Neurosci. 20:8435-8442PubMedGoogle Scholar
  270. Ono, K. and Han, J. 2000. The p38 signal transduction pathway: Activation and function. Cell Signal. 12:1-13PubMedCrossRefGoogle Scholar
  271. Pastorino, L., Sun, A., Lu, P.-J., Zhou, X.-Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S.-H., Li, X., Xia, W., Nicholson, L.K. and Lu, K.-P. 2006. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production. Nature 440:528-534PubMedCrossRefGoogle Scholar
  272. Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P. and Tsai, L.H. 1999. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615-622PubMedCrossRefGoogle Scholar
  273. Paudel, H.K., Lew, J., Ali, Z. and Wang, J.H. 1993. Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer’;s paired helical filaments. J. Biol. Chem. 268:23512-23518PubMedGoogle Scholar
  274. Paulus, W. and Selim, M. 1990. Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles. Acta Neuropathol. (Berlin) 81:89-94CrossRefGoogle Scholar
  275. Pearson, R.C.A., Esiri, M.M., Hiorns, R.W., Wilcock, G.K. and Powell, T.P.S. 1985. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc. Natl. Acad. Sci. USA 82:4531-4534PubMedCrossRefGoogle Scholar
  276. Pedersen, W.A., Cashman, N.R. and Mattson, M.P. 1999. The lipid peroxidation product 4-hydroxynonenal impairs glutamate and glucose transport and choline acetyltransferase activity in NSC-19 motor neuron cells. Exp. Neurol. 155:1-10PubMedCrossRefGoogle Scholar
  277. Pei, J.J., Sersen, E., Iqbal, K. and Grundke-Iqbal, I. 1994. Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. Brain Res. 655:70-76PubMedCrossRefGoogle Scholar
  278. Pei, J.J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B. and Cowburn, R.F. 2001. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer’;s disease brains at different stages of neurofibrillary degeneration. J. Alzheimer’;s Dis. 3:41-48Google Scholar
  279. Pei, J.J., Gong, C.X., An, W.L., Winblad, B., Cowburn, R.F., Grundke-Iqbal, I. and Iqbal, K. 2003. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer’;s disease. Am. J. Pathol. 163:845-858PubMedCrossRefGoogle Scholar
  280. Pike, C.J., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W. 1991. In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563:311-314PubMedCrossRefGoogle Scholar
  281. Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W. 1993. Neurodegeneration induced by β-amyloid peptides in vitro: The role of peptide assembly state. J. Neurosci. 13:1676-1687PubMedGoogle Scholar
  282. Pitas, R.E., Boyles, J.K., Lee, S.H., Foss, D. and Mahley, R.W. 1987. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917:148-161PubMedCrossRefGoogle Scholar
  283. Plum, L., Schubert, M. and Bruning, J.C. 2005. The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab. 16:59-65PubMedCrossRefGoogle Scholar
  284. Plyte, S.E., Hughes, K., Nikolakaki, E., Pulverer, B.J. and Woodgett, J.R. 1992. Glycogen synthase kinase-3: Functions in oncogenesis and development. Biochim. Biophys. Acta 1114:147-162PubMedGoogle Scholar
  285. Podlisny, M.B., Citron, M., Amarante, P., Sherrington, R., Xia, W., Zhang, J., Diehl, T., Levesque, G., Fraser, P., Haass, C., Koo, E.H., Seubert, P., St George-Hyslop, P., Teplow, D.B. and Selkoe, D.J. 1997. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol. Dis. 3:325-337PubMedCrossRefGoogle Scholar
  286. Poehlman, E.T. and Dvorak, R.V. 2000. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am. J. Clin. Nutr. 71:650S-655SPubMedGoogle Scholar
  287. Poon, R.Y., Lew, J. and Hunter, T. 1997. Identification of functional domains in the neuronal Cdk5 activator protein. J. Biol. Chem. 272:5703-5708PubMedCrossRefGoogle Scholar
  288. Popken, G.J., Hodge, R.D., Ye, P., Zhang, J., Ng, W., Kusky, J.R. and D’Ercole, A.J. 2004. In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. Eur. J. Neurosci. 19:2056-2068PubMedCrossRefGoogle Scholar
  289. Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., Flamez, P., Dequenne, A., Godaux, E., van Leuven, F. and Fahrenholz, F. 2004. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113:1456-1464PubMedGoogle Scholar
  290. Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T.C., Wang, R. and Ihara, Y. 2005. Longer forms of amyloid β protein: Implications for the mechanism of intramembrane cleavage by γ-secretase. J. Neurosci. 25:436-445PubMedCrossRefGoogle Scholar
  291. Qiu, W.Q., Ferreira, A., Miller, C., Koo, E.H. and Selkoe, D.J. 1995. Cell-surface β-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J. Neurosci. 15:2157-2167PubMedGoogle Scholar
  292. Raingeaud, J., Gupta, S., Rogers, J.S., Dickens, M., Han, J., Ulevitch, R.J. and Davis, R.J. 1995. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270:7420-7426PubMedCrossRefGoogle Scholar
  293. Refolo, L.M., Salton, S.R., Anderson, J.P., Mehta, P. and Robakis, N.K. 1989. Nerve and epidermal growth factors induce the release of the Alzheimer amyloid precursor from PC 12 cell cultures. Biochem. Biophys. Res. Commun. 164:664-670PubMedCrossRefGoogle Scholar
  294. Reiman, E.M., Caselli, R.J., Chen, K., Alexander, G.E., Bandy, D. and Frost, J. 2001. Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 98:3334-3339PubMedCrossRefGoogle Scholar
  295. Reiman, E.M., Chen, K., Alexander, G.E., Caselli, R.J., Bandy, D., Osborne, D., Saunders, A.M. and Hardy, J. 2004. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’;s dementia. Proc. Natl. Acad. Sci. USA 101:284-289PubMedCrossRefGoogle Scholar
  296. Rendon, A., Jung, D. and Jancsik, V. 1990. Interaction of microtubules and microtubule-associated proteins (MAPs) with rat brain mitochondria. Biochem. J. 269:555-556PubMedGoogle Scholar
  297. Reynolds, C.H., Nebreda, A.R., Gibb, G.M., Utton, M.A. and Anderton, B.H. 1997a. Reactivating kinase/p38 phosphorylates tau protein in vitro. J. Neurochem. 69:191-198CrossRefGoogle Scholar
  298. Reynolds, C.H., Utton, M.A., Gibb, G.M., Yates, A. and Anderton, B.H. 1997b. Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J. Neurochem. 68:1736-1744CrossRefGoogle Scholar
  299. Rostas, J.A. and Dunkley, P.R. 1992. Multiple forms and distribution of calcium/calmodulin-stimulated protein kinase II in brain. J. Neurochem. 59:1191-1202PubMedCrossRefGoogle Scholar
  300. Roux, P.P. and Blenis, J. 2004. ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68:320-344PubMedCrossRefGoogle Scholar
  301. Ryan, M., Starkey, M., Faull, R., Emson, P. and Bahn, S. 2001. Indexing-based differential display studies on post-mortem Alzheimer’;s brains. Brain Res. Mol. Brain Res. 88:199-202PubMedCrossRefGoogle Scholar
  302. Sadot, E., Jaaro, H., Seger, R. and Ginzburg, I. 1998. Ras-signaling pathways: Positive and negative regulation of tau expression in PC12 cells. J. Neurochem. 70:428-431PubMedCrossRefGoogle Scholar
  303. Sakashita, G., Shima, H., Komatsu, M., Urano, T., Kikuchi, A. and Kikuchi, K. 2003. Regulation of type 1 protein phosphatase/inhibitor-2 complex by glycogen synthase kinas-3β in intact cells. J. Biochem. (Tokyo) 133:165-171CrossRefGoogle Scholar
  304. Sandbrink, R., Masters, C.L. and Beyreuther, K. 1996. APP gene family. Alternative splicing generates functionally related isoforms. Ann. NY Acad. Sci. 777:281-287CrossRefGoogle Scholar
  305. Sang, H., Lu, Z., Li, Y., Ru, B., Wang, W. and Chen, J. 2001. Phosphorylation of tau by glycogen synthase kinase 3β in intact mammalian cells influences the stability of microtubules. Neurosci. Lett. 312:141-144PubMedCrossRefGoogle Scholar
  306. Sastre, M., Steiner, H., Fuchs, K., Capell, A., Multhaup, G., Condron, M.M., Teplow, D.B. and Haass, C. 2001. Presenilin-dependent γ-secretase processing of β-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2:835-841PubMedCrossRefGoogle Scholar
  307. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D. and Younkin, S. 1996. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’;s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’;s disease. Nat. Med. 2:864-870PubMedCrossRefGoogle Scholar
  308. Schipper, H.M., Cisse, S. and Stopa, E.G. 1995. Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann. Neurol. 37:758-768PubMedCrossRefGoogle Scholar
  309. Schipper, H.M., Liberman, A. and Stopa, E.G. 1998. Neural heme oxygenase-1 expression in idiopathic Parkinson’;s disease. Exp. Neurol. 150:60-68PubMedCrossRefGoogle Scholar
  310. Schubert, D. 2005. Glucose metabolism and Alzheimer’;s disease. Ageing Res. Rev. 4:240-257PubMedCrossRefGoogle Scholar
  311. Schubert, D., Jin, L.W., Saitoh, T. and Cole, G. 1989. The regulation of amyloid β protein precursor secretion and its modulatory role in cell adhesion. Neuron 3:689-694PubMedCrossRefGoogle Scholar
  312. Schubert, M., Brazil, D.P., Burks, D.J., Kushner, J.A., Ye, J., Flint, C.L., Farhang-Fallah, J., Dikkes, P., Warot, X.M., Rio, C., Corfas, G. and White, M.F. 2003. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J. Neurosci. 23:7084-7092PubMedGoogle Scholar
  313. Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D., Kondo, T., Alber, J., Galldiks, N., Kustermann, E., Arndt, S., Jacobs, A.H., Krone, W., Kahn, C.R. and Bruning, J.C. 2004. Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 101:3100-3105PubMedCrossRefGoogle Scholar
  314. Schulingkamp, R.J., Pagano, T.C., Hung, D. and Raffa, R.B. 2000. Insulin receptors and insulin action in the brain: Review and clinical implications. Neurosci. Biobehav. Rev. 24:855-872PubMedCrossRefGoogle Scholar
  315. Shackelford, D.A. 2006. DNA end joining activity is reduced in Alzheimer’;s disease. Neurobiol. Aging 27:596-605PubMedCrossRefGoogle Scholar
  316. Shah, S., Lee, S.F., Tabuchi, K., Hao, Y.H., Yu, C., La Plant, Q., Ball, H., Dann, C.E., III, Sudhof, T. and Yu, G. 2005. Nicastrin functions as a γ-secretase-substrate receptor. Cell 122:435-447PubMedCrossRefGoogle Scholar
  317. Shan, X. and Lin, C.L. 2006. Quantification of oxidized RNAs in Alzheimer’;s disease. Neurobiol. Aging 27:657-662PubMedCrossRefGoogle Scholar
  318. Shoji, M., Golde, T.E., Ghiso, J., Cheung, T.T., Estus, S., Shaffer, L.M., Cai, X.-D., McKay, D.M., Tintner, R., Frangione, B. and Younkin, S.G. 1992. Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258:126-129PubMedCrossRefGoogle Scholar
  319. Shpakov, A.O. and Pertseva, M.N. 2000. Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins. Membr. Cell. Biol. 13:455-484PubMedGoogle Scholar
  320. Shulman, R.G., Rothman, D.L., Behar, K.L. and Hyder, F. 2004. Energetic basis of brain activity: Implications for neuroimaging. Trends Neurosci. 27:489-495PubMedCrossRefGoogle Scholar
  321. Siegel, S.J., Bieschke, J., Powers, E.T. and Kelly, J.W. 2007. The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation. Biochemistry 46:1503-1510PubMedCrossRefGoogle Scholar
  322. Simpson, I.A., Chundu, K.R., Davies-Hill, T., Honer, W.G. and Davies, P. 1994. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’;s disease. Ann. Neurol. 35:546-551PubMedCrossRefGoogle Scholar
  323. Singh, T.J., Zaidi, T., Grundke-Iqbal, I. and Iqbal, K. 1996. Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. Mol. Cell. Biochem. 154:143-151PubMedCrossRefGoogle Scholar
  324. Skovronsky, D.M., Moore, D.B., Milla, M.E., Doms, R.W. and Lee, V.M. 2000. Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-Golgi network. J. Biol. Chem. 275:2568-2575PubMedCrossRefGoogle Scholar
  325. Small, G.W., Mazziotta, J.C., Collins, M.T., Baxter, L.R., Phelps, M.E., Mandelkern, M.A., Kaplan, A., La Rue, A., Adamson, C.F., Chang, L., Guze, B.H., Corder, E.H., Saunders, A.M., Haines, J.L., Pericak-Vance, M.A. and Roses, A.D. 1995. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. J. Am. Med. Assoc. 273:942-947CrossRefGoogle Scholar
  326. Small, G.W., Ercoli, L.M., Silverman, D.H., Huang, S.C., Komo, S., Bookheimer, S.Y., Lavretsky, H., Miller, K., Siddarth, P., Rasgon, N.L., Mazziotta, J.C., Saxena, S., Wu, H.M., Mega, M.S., Cummings, J.L., Saunders, A.M., Pericak-Vance, M.A., Roses, A.D., Barrio, J.R. and Phelps, M.E. 2000. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’;s disease. Proc. Natl. Acad. Sci. USA 97:6037-6042PubMedCrossRefGoogle Scholar
  327. Sorbi, S., Bird, E.D. and Blass, J.P. 1983. Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann. Neurol. 13:72-78PubMedCrossRefGoogle Scholar
  328. Sperber, B.R., Leight, S., Goedert, M. and Lee, V.M. 1995. Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells. Neurosci. Lett. 197:149-153PubMedCrossRefGoogle Scholar
  329. Spillantini, M.G., van Swieten, J.C. and Goedert, M. 2000. Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 2:193-205PubMedGoogle Scholar
  330. Stambolic, V., Ruel, L. and Woodgett, J.R. 1996. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6:1664-1668PubMedCrossRefGoogle Scholar
  331. Stein, T.D., Anders, N.J., De Carli, C., Chan, S.L., Mattson, M.P. and Johnson, J.A. 2004. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: Support for the amyloid hypothesis. J. Neurosci. 24:7707-7717PubMedCrossRefGoogle Scholar
  332. Steiner, B., Mandelkow, E.-M., Biernat, J., Gustke, N., Meyer, H.E., Schmidt, B., Mieskes, G., Söling, H.D., Drechsel, D., Kirschner, M.W., Goedert, M. and Mandelkow, E. 1990. Phosphorylation of microtubule-associated protein tau: Identification of the site for Ca2+-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J. 9:3539-3544PubMedGoogle Scholar
  333. Storey, E., Katz, M., Brickman, Y., Beyreuther, K. and Masters, C.L. 1999. Amyloid precursor protein of Alzheimer’;s disease: Evidence for a stable, full-length, trans-membrane pool in primary neuronal cultures. Eur. J. Neurosci. 11:1779-1788PubMedCrossRefGoogle Scholar
  334. Strittmatter, W.J., Weisgraber, K.H., Goedert, M., Saunders, A.M., Huang, D., Corder, E.H., Dong, L.-M., Jakes, R., Alberts, M.J., Gilbert, J.R., Han, S.-H., Hulette, C., Einstein, G., Schmechel, D.E., Pericak-Vance, M.A. and Roses, A.D. 1994. Hypothesis: Microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp. Neurol. 125:163-171PubMedCrossRefGoogle Scholar
  335. Subramaniam, R., Roediger, F., Jordan, B., Mattson, M.P., Keller, J.N., Waeg, G. and Butterfield, D.A. 1997. The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins. J. Neurochem. 69:1161-1169PubMedCrossRefGoogle Scholar
  336. Sultana, R., Poon, H.F., Cai, J., Pierce, W.M., Merchant, M., Klein, J.B., Markesbery, W.R. and Butterfield, D.A. 2006. Identification of nitrated proteins in Alzheimer’;s disease brain using a redox proteomics approach. Neurobiol. Dis. 22:76-87PubMedCrossRefGoogle Scholar
  337. Sun, X.J., Crimmins, D.L., Myers, M.G., Jr., Miralpeix, M. and White, M.F. 1993a. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol. Cell. Biol. 13:7418-7428Google Scholar
  338. Sun, F.F., Fleming, W.E. and Taylor, B.M. 1993b. Degradation of membrane phospholipids in the cultured human astroglial cell line UC-11MG during ATP depletion. Biochem. Pharmacol. 45:1149-1155CrossRefGoogle Scholar
  339. Sun, A., Liu, M., Nguyen, X.V. and Bing, G. 2003. P38 MAP kinase is activated at early stages in Alzheimer’;s disease brain. Exp. Neurol. 183:394-405PubMedCrossRefGoogle Scholar
  340. Takashima, A. 2006. GSK-3 is essential in the pathogenesis of Alzheimer’;s disease. J. Alzheimer’;s Dis. 9:309-317Google Scholar
  341. Takeda, A., Perry, G., Abraham, N.G., Dwyer, B.E., Kutty, R.K., Laitinen, J.T., Petersen, R.B. and Smith, M.A. 2000a. Overexpression of heme oxygenase in neuronal cells, the possible interaction with tau. J. Biol. Chem. 275:5395-5399CrossRefGoogle Scholar
  342. Takeda, A., Smith, M.A., Avila, J., Nunomura, A., Siedlak, S.L., Zhu, X., Perry, G. and Sayre, L.M. 2000b. In Alzheimer’;s disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J. Neurochem. 75:1234-1241CrossRefGoogle Scholar
  343. Tanaka, C. and Nishizuka, Y. 1994. The protein kinase C family for neuronal signaling. Annu. Rev. Neurosci. 17:551-567PubMedCrossRefGoogle Scholar
  344. Tang, D. and Wang, J.-H. 1996. Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. Prog. Cell Cycle Res. 2:205-216PubMedCrossRefGoogle Scholar
  345. Tanzi, R.E., McClatchey, A.I., Lamperti, E.D., Villa-Komaroff, L., Gusella, J.F. and Neve, R.L. 1988. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’;s disease. Nature 331:528-530PubMedCrossRefGoogle Scholar
  346. Tanzi, R.E., Vaula, G., Romano, D.M., Mortilla, M., Huang, T.L., Tupler, R.G., Wasco, W., Hyman, B.T., Haines, J.L., Jenkins, B.J. and et al. 1992. Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am. J. Hum. Genet. 51:273-282PubMedGoogle Scholar
  347. Tesseur, I., van Dorpe, J., Bruynseels, K., Bronfman, F., Sciot, R., van Lommel, A. and van Leuven, F. 2000a. Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am. J. Pathol. 157:1495-1510CrossRefGoogle Scholar
  348. Tesseur, I., van Dorpe, J., Spittaels, K., van den Haute, C., Moechars, D. and van Leuven, F. 2000b. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am. J. Pathol. 156:951-964CrossRefGoogle Scholar
  349. Thinakaran, G., Borchelt, D.R., Lee, M.K., Slunt, H.H., Spitzer, L., Kim, G., Ratovitsky, T., Davenport, F., Nordstedt, C., Seeger, M., Hardy, J., Levey, A.I., Gandy, S.E., Jenkins, N.A., Copeland, N.G., Price, D.L. and Sisodia, S.S. 1996. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181-190PubMedCrossRefGoogle Scholar
  350. Trakshel, G.M., Kutty, R.K. and Maines, M.D. 1988. Resolution of the rat brain heme oxygenase activity: Absence of a detectable amount of the inducible form (HO-1). Arch. Biochem. Biophys. 260:732-739PubMedCrossRefGoogle Scholar
  351. Trojanowski, J.Q. and Lee, V.M. 1995. Phosphorylation of paired helical filament tau in Alzheimer’;s disease neurofibrillary lesions: Focusing on phosphatases. FASEB J. 9:1570-1576PubMedGoogle Scholar
  352. Trojanowski, J.Q., Mawal-Dewan, M., Schmidt, M.L., Martin, J. and Lee, V.M.-Y. 1993. Localization of the mitogen activated protein kinase ERK2 in Alzheimer’;s disease neurofibrillary tangles and senile plaque neurites. Brain Res. 618:333-337PubMedCrossRefGoogle Scholar
  353. Tsai, L.H., Delalle, I., Caviness, V.S., Jr., Chae, T. and Harlow, E. 1994. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419-423PubMedCrossRefGoogle Scholar
  354. Vanier, M.T., Neuville, P., Michalik, L. and Launay, J.F. 1998. Expression of specific tau exons in normal and tumoral pancreatic acinar cells. J. Cell Sci. 111:1419-1432PubMedGoogle Scholar
  355. Veeranna, Amin, N.D., Ahn, N.G., Jaffe, H., Winters, C.A., Grant, P. and Pant, H.C. 1998. Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J. Neurosci. 18:4008-4021PubMedGoogle Scholar
  356. Vincent, I.J. and Davies, P. 1992. A protein kinase associated with paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. USA 89:2878-2882PubMedCrossRefGoogle Scholar
  357. Vogelsberg-Ragaglia, V., Schuck, T., Trojanowski, J.Q. and Lee, V.M. 2001. PP2A mRNA expression is quantitatively decreased in Alzheimer’;s disease hippocampus. Exp. Neurol. 168:402-412PubMedCrossRefGoogle Scholar
  358. Walsh, D.M., Hartley, D.M., Condron, M.M., Selkoe, D.J. and Teplow, D.B. 2001. In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the ætiology of Flemish variant (Ala692-- > Gly) Alzheimer’;s disease. Biochem. J. 355:869-877PubMedGoogle Scholar
  359. Walter, J., Capell, A., Grunberg, J., Pesold, B., Schindzielorz, A., Prior, R., Podlisny, M.B., Fraser, P., Hyslop, P.S., Selkoe, D.J. and Haass, C. 1996. The Alzheimer’;s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol. Med. 2:673-691PubMedGoogle Scholar
  360. Walton, H.S. and Dodd, P.R. 2007. Glutamate-glutamine cycling in Alzheimer’;s disease. Neurochem. Int. 50(7-8):1052-1066PubMedCrossRefGoogle Scholar
  361. Wang, J., Xiong, S., Xie, C., Markesbery, W.R. and Lovell, M.A. 2005. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’;s disease. J. Neurochem. 93:953-962PubMedCrossRefGoogle Scholar
  362. Wang, J.-Z., Wu, Q., Smith, A., Grundke-Iqbal, I. and Iqbal, K. 1998. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett. 436:28-34PubMedCrossRefGoogle Scholar
  363. Wang, J.-Z., Grundke-Iqbal, I. and Iqbal, K. 2007. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur. J. Neurosci. 25:59-68PubMedCrossRefGoogle Scholar
  364. Weidemann, A., Eggert, S., Reinhard, F.B., Vogel, M., Paliga, K., Baier, G., Masters, C.L., Beyreuther, K. and Evin, G. 2002. A novel ε-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41:2825-2835PubMedCrossRefGoogle Scholar
  365. Wells, L., Vosseller, K. and Hart, G.W. 2001. Glycosylation of nucleocytoplasmic proteins: Signal transduction and O-GlcNAc. Science 291:2376-2378PubMedCrossRefGoogle Scholar
  366. Werther, G.A., Hogg, A., Oldfield, B.J., McKinley, M.J., Figdor, R., Allen, A.M. and Mendelsohn, F.A. 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
  367. Williamson, R., Scales, T., Clark, B.R., Gibb, G., Reynolds, C.H., Kellie, S., Bird, I.N., Varndell, I.M., Sheppard, P.W., Everall, I. and Anderton, B.H. 2002. Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-β peptide exposure: Involvement of Src family protein kinases. J. Neurosci. 22:10-20PubMedGoogle Scholar
  368. Wimo, A., Jonsson, L. and Winblad, B. 2006. An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement. Geriatr. Cogn. Disord. 21:175-181PubMedCrossRefGoogle Scholar
  369. Wolfe, M.S., Xia, W., Moore, C.L., Leatherwood, D.D., Ostaszewski, B., Rahmati, T., Donkor, I.O. and Selkoe, D.J. 1999a. Peptidomimetic probes and molecular modeling suggest that Alzheimer’;s γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38:4720-4727CrossRefGoogle Scholar
  370. Wolfe, M.S., Xia, W., Ostaszewski, B.L., Diehl, T.S., Kimberly, W.T. and Selkoe, D.J. 1999b. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398:513-517CrossRefGoogle Scholar
  371. Woodgett, J.R. 1990. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9:2431-2438PubMedGoogle Scholar
  372. Wozniak, M., Rydzewski, B., Baker, S.P. and Raizada, M.K. 1993. The cellular and physiological actions of insulin in the central nervous system. Neurochem. Int. 22:1-10PubMedCrossRefGoogle Scholar
  373. Xiao, J., Perry, G., Troncoso, J. and Monteiro, M.J. 1996. α-Calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’;s disease. J. Neuropathol. Exp. Neurol. 55:954-963PubMedCrossRefGoogle Scholar
  374. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., van Bronswijk, W. and Martins, R. 2002. Alzheimer’;s β-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci. 22:RC21Google Scholar
  375. Xu, R.-M., Carmel, G., Sweet, R.M., Kuret, J. and Cheng, X. 1995. Crystal structure of casein kinase-1, a phosphate-directed protein kinase. EMBO J. 14:1015-1023PubMedGoogle Scholar
  376. Yamamoto, H., Fukunaga, K., Tanaka, E. and Miyamoto, E. 1983. Ca2+- and calmodulin-dependent phosphorylation of microtubule-associated protein 2 and tau factor, and inhibition of microtubule assembly. J. Neurochem. 41:1119-1125PubMedCrossRefGoogle Scholar
  377. Yamamoto, H., Fukunaga, K., Goto, S., Tanaka, E. and Miyamoto, E. 1985. Ca2+, calmodulin-dependent regulation of microtubule formation via phosphorylation of microtubule-associated protein 2, tau factor, and tubulin, and comparison with the cyclic AMP-dependent phosphorylation. J. Neurochem. 44:759-768PubMedCrossRefGoogle Scholar
  378. Yamamoto, H., Saitoh, Y., Fukunaga, K., Nishimura, H. and Miyamoto, E. 1988. Dephosphorylation of microtubule proteins by brain protein phosphatases 1 and 2A, and its effect on microtubule assembly. J. Neurochem. 50:1614-1623PubMedCrossRefGoogle Scholar
  379. Yamamoto, H., Hiragami, Y., Murayama, M., Ishizuka, K., Kawahara, M. and Takashima, A. 2005. Phosphorylation of tau at serine 416 by Ca2+calmodulin-dependent protein kinase II in neuronal soma in brain. J. Neurochem. 94:1438-1447PubMedCrossRefGoogle Scholar
  380. Yamazaki, T., Koo, E.H. and Selkoe, D.J. 1997. Cell surface amyloid β-protein precursor colocalizes with β1 integrins at substrate contact sites in neural cells. J. Neurosci. 17:1004-1010PubMedGoogle Scholar
  381. Yasojima, K., Kuret, J., DeMaggio, A.J., McGeer, E. and McGeer, P.L. 2000. Casein kinase 1δ mRNA is upregulated in Alzheimer disease brain. Brain Res. 865:116-120PubMedCrossRefGoogle Scholar
  382. Ye, S., Huang, Y., Mullendorff, K., Dong, L., Giedt, G., Meng, E.C., Cohen, F.E., Kuntz, I.D., Weisgraber, K.H. and Mahley, R.W. 2005. Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target. Proc. Natl. Acad. Sci. USA 102:18700-18705PubMedCrossRefGoogle Scholar
  383. Yoshida, H., Hastie, C.J., McLauchlan, H., Cohen, P. and Goedert, M. 2004. Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK). J. Neurochem. 90:352-358PubMedCrossRefGoogle Scholar
  384. Zhang, J. and Piantadosi, C.A. 1992. Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J. Clin. Invest. 90:1193-1199PubMedCrossRefGoogle Scholar
  385. Zhang, C., Lambert, M.P., Bunch, C., Barber, K., Wade, W.S., Krafft, G.A. and Klein, W.L. 1994. Focal adhesion kinase expressed by nerve cell lines shows increased tyrosine phosphorylation in response to Alzheimer’;s Aβ peptide. J. Biol. Chem. 269:25247-25250PubMedGoogle Scholar
  386. Zhang, F., Phiel, C.J., Spece, L., Gurvich, N. and Klein, P.S. 2003. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 278:33067-33077PubMedCrossRefGoogle Scholar
  387. Zhao, G., Cui, M.Z., Mao, G., Dong, Y., Tan, J., Sun, L. and Xu, X. 2005. γ-Cleavage is dependent on ζ-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J. Biol. Chem. 280:37689-37697PubMedCrossRefGoogle Scholar
  388. Zheng, W.H., Kar, S., Dore, S. and Quirion, R. 2000. Insulin-like growth factor-1 (IGF-1): A neuroprotective trophic factor acting viathe Akt kinase pathway. J. Neural Transm. Suppl.:261-272Google Scholar
  389. Zheng-Fischhofer, Q., Biernat, J., Mandelkow, E.M., Illenberger, S., Godemann, R. and Mandelkow, E. 1998. Sequential phosphorylation of tau by glycogen synthase kinase-3β and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur. J. Biochem. 252:542-552PubMedCrossRefGoogle Scholar
  390. Zhou, S., Zhou, H., Walian, P.J. and Jap, B.K. 2005. CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer’;s disease amyloid β-peptide production. Proc. Natl. Acad. Sci. USA 102:7499-7504PubMedCrossRefGoogle Scholar
  391. Zhu, X., Rottkamp, C.A., Boux, H., Takeda, A., Perry, G. and Smith, M.A. 2000a. Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J. Neuropathol. Exp. Neurol. 59:880-888Google Scholar
  392. Zhu, X., Rottkamp, C.A., Raina, A.K., Brewer, G.J., Ghanbari, H.A., Boux, H. and Smith, M.A. 2000b. Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiol. Aging 21:807-813CrossRefGoogle Scholar
  393. Zhu, X., Raina, A.K., Rottkamp, C.A., Aliev, G., Perry, G., Boux, H. and Smith, M.A. 2001a. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’;s disease. J. Neurochem. 76:435-441CrossRefGoogle Scholar
  394. Zhu, X., Rottkamp, C.A., Hartzler, A., Sun, Z., Takeda, A., Boux, H., Shimohama, S., Perry, G. and Smith, M.A. 2001b. Activation of MKK6, an upstream activator of p38, in Alzheimer’;s disease. J. Neurochem. 79:311-318CrossRefGoogle Scholar
  395. Zhu, X., Lee, H.G., Raina, A.K., Perry, G. and Smith, M.A. 2002. The role of mitogen-activated protein kinase pathways in Alzheimer’;s disease. Neurosignals 11:270-281PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Florian M. Gebhardt
    • 1
  • Peter R. Dodd
    • 1
  1. 1.School of Molecular and Microbial SciencesUniversity of QueenslandBrisbaneAustralia

Personalised recommendations