Molecular Neurobiology

, Volume 26, Issue 2–3, pp 299–316 | Cite as

Intracellular A-beta amyloid, A sign for worse things to come?



In this review the authors discuss the possible neuropathological role of intracellular amyloid-β accumulation in Alzheimer’s disease (AD) pathology. There is abundant evidence that at early stages of the disease, prior to Aβ amyloid plaque formation, Aβ peptides accumulate intraneuronally in the cerebral cortex and the hippocampus. The experimental evidence would indicate that intracellular amyloid-β could originate both by intracellular biosynthesis and also from the uptake of amyloidogenic peptides from the extracellular milieu. Herein the aspects of the possible impact of intracellular amyloid-β in human AD pathology are discussed, as well as recent observations from a rat transgenic model with a phenotype of intracellular accumulation of Aβ fragments in neurons of the hippocampus and cortex, without plaque formation. In this model, the intracellular amyloid-β phenotype is accompanied by increased MAPK/ERK activity and tau hyperphosphorylation. Finally, the authors discuss the hypothesis that, prior to plaque formation, intracellular Aβ accumulation induces biochemical and pathological changes in the brain at the cellular level priming neurons to further cytotoxic attack of extracellular amyloidogenic peptides.

Index Entries

Alzheimer’s disease tau phosphorylation Aβ transgenic rats 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sadovnick, D. and Lovestone, S. (2001) Genetic counselling, in Clinical Diagnosis and Management of Alzheimer’s Disease? (Gauthier, S., ed.) Martin Dunitz, London, pp. 355–365.Google Scholar
  2. 2.
    Terry, R. D., Masliah, E., and Hansen, L. A. (1999) The neuropathology of Alzheimer’s disease and the structural basis of its cognitive alterations, in Alzheimer’s Disease (Terry, R. D., Katzman, R., and Bick, K. L., eds.) Raven Press, New York, pp. 187–206.Google Scholar
  3. 3.
    Goedert, M. (1998) Neurofibrillary pathology of Alzheimer’s disease and other tauopathies Prog. Brain Res. 117, 287–306.PubMedGoogle Scholar
  4. 4.
    Avila, J., Lim, F., Moreno, F., Belmonte, C., and Cuello, A. C. (2002) Tau function and dysfunction in neurons: its role in neurodegenerative disorders. Mol. Neurobiol. (In press.)Google Scholar
  5. 5.
    Haass, C., Schlossmacher, M. G., Hung, A. Y., et al. (1992) Amyloid b-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325.PubMedGoogle Scholar
  6. 6.
    Shoji, M., Golde, T. E., Ghiso, J., et al. (1992) Production of the Alzheimer amyloid b protein by normal proteolytic processing. Science 258, 126–129.PubMedGoogle Scholar
  7. 7.
    Walter, J., Kaether, C., Steiner, H., and Haass, C. (2001) The cell biology of Alzheimer’s disease: uncovering the secrets of secretases. Curr. Opin. Neurobiol. 11, 585–590.PubMedGoogle Scholar
  8. 8.
    Vassar, R. and Citron, M. (2000) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 27, 419–422.PubMedGoogle Scholar
  9. 9.
    Tamaoka, A., Sawamura, N., Odaka, A., Suzuki, N., Mizusawa, H., Shoji, S., and Mori, H. (1995) Amyloid beta protein 1-42/43 (A beta 1-42/43) in cerebellar diffuse plaques: enzymelinked immunosorbent assay and immunocytochemical study. Brain Res. 679, 151–156.PubMedGoogle Scholar
  10. 10.
    Citron, M., Oltersdorf, T., Haass, C., et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360, 672–674.PubMedGoogle Scholar
  11. 11.
    Hardy, J. (1999) The shorter amyloid cascade hypothesis. Neurobiol. Aging 20, p. 85.PubMedGoogle Scholar
  12. 12.
    Selkoe, D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766.PubMedGoogle Scholar
  13. 13.
    Goate, A., Chartier-Harlin, M. C., Mullan, M., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.PubMedGoogle Scholar
  14. 14.
    Sherrington, R., Rogaev, E. I., Liang, Y., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.PubMedGoogle Scholar
  15. 15.
    Rogaev, E. I., Sherrington, R., Rogaeva, E. A., et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778.PubMedGoogle Scholar
  16. 16.
    Levy-Lahad, E., Wasco, W., Poorkaj, P., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.PubMedGoogle Scholar
  17. 17.
    Corder, E. H., Saunders, A. M., Strittmatter, W. J., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923.PubMedGoogle Scholar
  18. 18.
    Strittmatter, W. J. (2000) Apolipoprotein E and Alzheimer’s disease. Ann. NY Acad. Sci. 924, 91–92.PubMedGoogle Scholar
  19. 19.
    Poirier, J. (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci. 17, 525–530.PubMedGoogle Scholar
  20. 20.
    Bales, K. R., Verina, T., Dodel, R. C., et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263–264.PubMedGoogle Scholar
  21. 21.
    Poirier, J. (2000) Apolipoprotein E and Alzheimer’s disease. A role in amyloid catabolism. Ann. NY Acad. Sci. 924, 81–90.PubMedGoogle Scholar
  22. 22.
    Blacker, D. and Tanzi, R. E. (1998) The genetics of Alzheimer disease: current status and future prospects. Arch. Neurol. 55, 294–296.PubMedGoogle Scholar
  23. 23.
    Nicoll, J. A., Mrak, R. E., Graham, D. I., et al. (2000) Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann. Neurol. 47, 365–368.PubMedGoogle Scholar
  24. 24.
    Papassotiropoulos, A., Bagli, M., Feder, O., et al. (1999) Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer’s disease. Neurosci. Lett. 262, 171–174.PubMedGoogle Scholar
  25. 25.
    Kamboh, M. I., Ferrell, R. E., and DeKosky, S. T. (1998) Genetic association studies between Alzheimer’s disease and two polymorphisms in the low density lipoprotein receptor-related protein gene. Neurosci. Lett. 244, 65–68.PubMedGoogle Scholar
  26. 26.
    Yamanaka, H., Kamimura, K., Tanahashi, H., Takahashi, K., Asada, T., and Tabira, T. (1998) Genetic risk factors in Japanese Alzheimer’s disease patients: alphal-ACT, VLDLR, and ApoE Neurobiol. Aging 19, S43-S46.Google Scholar
  27. 27.
    Hu, Q., Kukull, W. A., Bressler, S. L., Gray, M. D., Cam, J. A., Larson, E. B., Martin, G. M., and Deeb, S. S. (1998) The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type. Hum. Genet. 103, 295–303.PubMedGoogle Scholar
  28. 28.
    Montoya, S. E., Aston, C. E., DeKosky, S. T., Kamboh, M. I., Lazo, J. S., and Ferrell, R. E. (1998) Bleomycin hydrolase is associated with risk of sporadic Alzheimer’s disease. Nat. Genet. 18, 211–212.PubMedGoogle Scholar
  29. 29.
    Finckh, U., von der, K. H., Velden, J., et al. (2000) Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease. Arch. Neurol. 57, 1579–1583.PubMedGoogle Scholar
  30. 30.
    Jaffe, A. B., Toran-Allerand, C. D., Greengard, P., and Gandy, S. E. (1994) Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J. Biol. Chem. 269, 13,065–13,068.Google Scholar
  31. 31.
    Tang, M. X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., Andrews, H., and Mayeux, R. (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348, 429–432.PubMedGoogle Scholar
  32. 32.
    Xu, H., Sweeney, D., Wang, R., Thinakaran, G., Lo, A. C., Sisodia, S. S., Greengard, P., and Gandy, S. (1997) Generation of Alzheimer bamyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc. Natl. Acad. Sci. USA 94, 3748–3752.PubMedGoogle Scholar
  33. 33.
    Zheng, H., Xu, H., Uljon, S. N., et al. (2002) Modulation of A(beta) peptides by estrogen in mouse models. J. Neurochem. 80, 191–196.PubMedGoogle Scholar
  34. 34.
    Chang, D., Kwan, J. and Timiras, P. S. (1997) Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. Adv. Exp. Med. Biol. 429, 261–271.PubMedGoogle Scholar
  35. 35.
    Mattson, M. P. and Chan, S. L. (2001) Dysregulation of cellular calcium homeostasis in Alzheimer’s disease: bad genes and bad habits. J. Mol. Neurosci. 17, 205–224.PubMedGoogle Scholar
  36. 36.
    Mattson, M. P. (2000) Neuroprotective signaling and the aging brain: take away my food and let me run. Brain Res. 886, 47–53.PubMedGoogle Scholar
  37. 37.
    Borchelt, D. R., Thinakaran, G., Eckman, C. B., et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.PubMedGoogle Scholar
  38. 38.
    Fraser, P. E., Yang, D. S., Yu, G., et al. (2000) Presenilin structure, function and role in Alzheimer disease. Biochim. Biophys. Acta. 1502, 1–15.PubMedGoogle Scholar
  39. 39.
    Chartier-Harlin, M. C., Crawford, F., Houlden, H., et al. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353, 844–846.PubMedGoogle Scholar
  40. 40.
    Haass, C., Lemere, C. A., Capell, A., et al. (1995) The Swedish mutation causes earlyonset Alzheimer’s disease by beta-secretase cleavage within the secretory pathway. Nat. Med. 1, 1291–1296.PubMedGoogle Scholar
  41. 41.
    Citron, M., Westaway, D., Xia, W., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72.PubMedGoogle Scholar
  42. 42.
    Glabe, C. (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J. Mol. Neurosci. 17, 137–145.PubMedGoogle Scholar
  43. 43.
    Burger, P. C. and Vogel, F. S. (1973) The development of the pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am. J. Pathol. 73, 457–476.PubMedGoogle Scholar
  44. 44.
    Whalley, L. J. (1982) The dementia of Down’s syndrome and its relevance to aetiological studies of Alzheimer’s disease. Ann. NY Acad. Sci. 396, 39–53.PubMedGoogle Scholar
  45. 45.
    Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245–4249.PubMedGoogle Scholar
  46. 46.
    Wisniewski, K. E., Wisniewski, H. M., and Wen, G. Y. (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann. Neurol. 17, 278–282.PubMedGoogle Scholar
  47. 47.
    Mann, D. M., Yates, P. O., Marcyniuk, B., and Ravindra, C. R. (1986) The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol. Appl. Neurobiol. 12, 447–457.PubMedGoogle Scholar
  48. 48.
    Cork, L. C. (1990) Neuropathology of Down syndrome and Alzheimer disease. Am. J. Med. Genet. Suppl 7, 282–286.Google Scholar
  49. 49.
    Fukuoka, Y., Fujita, T., and Ito, H. (1990) Histopathological studies on senile plaques in brains of patients with Down’s syndrome Kobe. J. Med. Sci. 36, 153–171.Google Scholar
  50. 50.
    Hof, P. R., Bouras, C., Perl, D. P., Sparks, D. L., Mehta, N., and Morrison, J. H. (1995) Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Quantitative regional analysis and comparison with Alzheimer’s disease. Arch. Neurol. 52, 379–391.PubMedGoogle Scholar
  51. 51.
    Hyman, B. T., West, H. L., Rebeck, G. W., Lai, F., and Mann, D. M. (1995) Neuropathological changes in Down’s syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. Arch. Neurol. 52, 373–378.PubMedGoogle Scholar
  52. 52.
    Mann, D. M., Prinja, D., Davies, C. A., et al. (1989) Immunocytochemical profile of neurofibrillary tangles in Down’s syndrome patients of different ages. J. Neurol. Sci. 92, 247–260.PubMedGoogle Scholar
  53. 53.
    Alvarez, A., Toro, R., Caceres, A., and Maccioni, R. B. (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett. 459, 421–426.PubMedGoogle Scholar
  54. 54.
    Morishima, Y., Gotoh, Y., Zieg, J., et al. (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J. Neurosci. 21, 7551–7560.PubMedGoogle Scholar
  55. 55.
    Sheng, J. G., Jones, R. A., Zhou, X. Q., McGinness, J. M., Van Eldik, L. J., Mrak, R. E., and Griffin, W. S. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylation. Neurochem. Int. 39, 341–348.PubMedGoogle Scholar
  56. 56.
    Zhu, X., Castellani, R. J., Takeda, A., Nunomura, A., Atwood, C. S., Perry, G., and Smith, M. A. (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech. Ageing Dev. 123, 39–46.PubMedGoogle Scholar
  57. 57.
    Zhu, X., Rottkamp, C. A., Hartzler, A., et al. (2001) Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease. J. Neurochem. 79, 311–318.PubMedGoogle Scholar
  58. 58.
    Checler, F., da Costa, C. A., Ancolio, K., Chevallier, N., Lopez-Perez, E., and Marambaud, P. (2000) Role of the proteasome in Alzheimer’s disease. Biochim. Biophys. Acta. 1502, 133–138.PubMedGoogle Scholar
  59. 59.
    McGeer, P. L. and McGeer, E. G. (1992) Complement proteins and complement inhibitors in Alzheimer’s disease. Res. Immunol. 143, 621–624.PubMedGoogle Scholar
  60. 60.
    Emmerling, M. R., Watson, M. D., Raby, C. A., and Spiegel, K. (2000) The role of complement in Alzheimer’s disease pathology. Biochim. Biophys. Acta. 1502, 158–171.PubMedGoogle Scholar
  61. 61.
    Smith, M. A., Rottkamp, C. A., Nunomura, A., Raina, A. K., and Perry, G. (2000) Oxidative stress in Alzheimer’s disease. Biochim. Biophys. Acta. 1502, 139–144.PubMedGoogle Scholar
  62. 62.
    Varadarajan, S., Yatin, S., Aksenova, M., and Butterfield, D. A. (2000) Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J. Struct. Biol. 130, 184–208.PubMedGoogle Scholar
  63. 63.
    Numomura, A., Perry, G., Aliev, G., et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767.Google Scholar
  64. 64.
    Nixon, R. A., Mathews, P. M. and Ctaldo, A. M. (2001) The neuronal endosomal-lysosomal system in Alzheimer’s disease. J. Alz. Dis. 3, 97–107.Google Scholar
  65. 65.
    Casley, C. S., Canevari, L., Land, J. M., Clark, J. B., and Sharpe, M. A. (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J. Neurochem. 80, 91–100.PubMedGoogle Scholar
  66. 66.
    Grant, S. M., Morinville, A., Maysinger, D., Szyf, M., and Cuello, A. C. (1999) Phosporylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform. Mol. Brain Res. 72, 115–120.PubMedGoogle Scholar
  67. 67.
    Canevari, L., Clark, J. B., and Bates, T. E. (1999) Beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett. 457, 131–134.PubMedGoogle Scholar
  68. 68.
    Parks, J. K., Smith, T. S., Trimmer, P. A., Bennett, J. P., Jr. and Parker, W. D., Jr. (2001) Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J. Neurochem. 76, 1050–1056.PubMedGoogle Scholar
  69. 69.
    Harkany, T., Hortobagyi, T., Sasvari, M., Konya, C., Penke, B., Luiten, P. G., and Nyakas, C. (1999) Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: relevance to Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 963–1008.PubMedGoogle Scholar
  70. 70.
    Auld, D. S., Kar, S., and Quirion, R. (1998) Beta-amyloid peptides as direct cholinergic neuromodulators: a missing link? Trends Neurosci. 21, 43–49.PubMedGoogle Scholar
  71. 71.
    Kar, S., Seto, D., Gaudreau, P., and Quirion, R. (1996) Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices. J. Neurosci. 16, 1034–1040.PubMedGoogle Scholar
  72. 72.
    Laskay, G., Zarandi, M., Varga, J., Jost, K., Fonagy, A., Torday, C., Latzkovits, L., and Penke, B. (1997) A putative tetrapeptide antagonist prevents beta-amyloid-induced long-term elevation of [Ca2+]i in rat astrocytes. Biochem. Biophys. Res. Commun. 235, 479–481.PubMedGoogle Scholar
  73. 73.
    Lin, H., Bhatia, R., and Lal, R. (2001) Amyloid beta protein forms ion channels: implications for Alzheimer’s disease pathophysiology. FASEB J. 15, 2433–2444.PubMedGoogle Scholar
  74. 74.
    Mattson, M. P., Barger, S. W., Cheng, B., Lieberburg, I., Smith-Swintosky, V. L., and Rydel, R. E. (1993) Beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. Trends Neurosci. 16, 419–414.Google Scholar
  75. 75.
    Mattson, M. P. and Pedersen, W. A. (1998) Effects of amyloid precursor protein derivatives and oxidative stress on basal forebrain cholinergic systems in Alzheimer’s disease. Int. J. Dev. Neurosci. 16, 737–753.PubMedGoogle Scholar
  76. 76.
    Tong, L., Thornton, P. L., Balazs, R., and Cotman, C. W. (2001) Beta-amyloid (1–42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival is not compromised. J. Biol. Chem. 276, 17,301–17,306.Google Scholar
  77. 77.
    Ferrer, I., Blanco, R., Carmona, M., Puig, B., Dominguez, I., and Vinals, F. (2002) Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. Acta. Neuropathol. (Berl.) 103, 391–407.Google Scholar
  78. 78.
    Cummings, B. J., Pike, C. J., Shankle, R., and Cotman, C. W. (1996) Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer’s disease. Neurobiol. Aging 17, 921–933.PubMedGoogle Scholar
  79. 79.
    Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., and Cole, G. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.PubMedGoogle Scholar
  80. 80.
    Naslund, J., Haroutunian, V., Mohs, R., Davis, K. L., Davies, P., Greengard, P., and Buxbaum, J. D. (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283, 1571–1577.PubMedGoogle Scholar
  81. 81.
    Chen, G., Chen, K. S., Knox, J., et al. (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408, 975–979.PubMedGoogle Scholar
  82. 82.
    Gordon, M. N., King, D. L., Diamond, D. M., et al. (2001) Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 mice. Neurobiol. Aging 22, 377–385.PubMedGoogle Scholar
  83. 83.
    Frautschy, S. A., Baird, A., and Cole, G. M. (1991) Effects of injected Alzheimer b-amyloid cores in rat brain. Proc. Natl. Acad. Sci. USA 88, 8362–8366.PubMedGoogle Scholar
  84. 84.
    Winkler, J., Connor, D. J., Frautschy, S. A., Behl, C., Waite, J. J., Cole, G. M., and Thal, L. J. (1994) Lack of long-term effects after beta-amyloid protein injections in rat brain. Neurobiol. Aging 15, 601–607.PubMedGoogle Scholar
  85. 85.
    Giovannelli, L., Casamenti, F., Scali, C., Bartolini, L., and Pepeu, G. (1995) Differential effects of amyloid peptides beta-(1–40) and beta-(25–35) injections into the rat nucleus basalis. Neuroscience 66, 781–792.PubMedGoogle Scholar
  86. 86.
    Giovannelli, L., Scali, C., Faussone-Pellegrini, M. S., Pepeu, G., and Casamenti, F. (1998) Long-term changes in the aggregation state and toxic effects of beta-amyloid injected into the rat brain. Neuroscience 87, 349–357.PubMedGoogle Scholar
  87. 87.
    Rush, D. K., Aschmies, S., and Merriman, M. C. (1992) Intracerebral beta-amyloid (25–35) produces tissue damage: is it neurotoxic? Neurobiol. Aging 13, 591–594.PubMedGoogle Scholar
  88. 88.
    Koistinaho, M., Ort, M., Cimadevilla, J. M., Vondrous, R., Cordell, B., Koistinaho, J., Bures, J., and Higgins, L. S. (2001) Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid deposits but do not form plaques. Proc. Natl. Acad. Sci. USA 98, 14,675–14,680.Google Scholar
  89. 89.
    Parvathy, S., Davies, P., Haroutunian, V., et al. (2001) Correlation between Abetax-40-, Abetax-42-, and Abetax-43-containing amyloid plaques and cognitive decline. Arch. Neurol. 58, 2025–2032.PubMedGoogle Scholar
  90. 90.
    Stephan, A., Laroche, S., and Davis, S. (2001) Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits. J. Neurosci. 21, 5703–5714.PubMedGoogle Scholar
  91. 91.
    Janus, C., Chishti, M. A., and Westaway, D. (2000) Transgenic mouse models of Alzheimer’s disease. Biochim. Biophys. Acta. 1502, 63–75.PubMedGoogle Scholar
  92. 92.
    Morgan, D., Diamond, D. M., Gottschall, P. E., et al. (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408, 982–985.PubMedGoogle Scholar
  93. 93.
    Mobley, W. C., Neve, R. L., Prusiner, S. B., and McKinley, M. P. (1988) Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain. Proc. Natl. Acad. Sci. USA 85, 9811–9815.PubMedGoogle Scholar
  94. 94.
    Rossner, S., Ueberham, U., Schliebs, R., Perez-Polo, J. R., and Bigl, V. (1998) The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling. Prog. Neurobiol. 56, 541–569.PubMedGoogle Scholar
  95. 95.
    Quon, D., Catalano, R., and Cordell, B. (1990) Fibroblast growth factor induces beta-amyloid precursor mRNA in ghal but not neuronal cultured cells. Biochem. Biophys. Res. Commun. 167, 96–102.PubMedGoogle Scholar
  96. 96.
    Caporaso, G. L., Gandy, S. E., Buxbaum, J. D., Ramabhadran, T. V., and Greengard, P. (1992) Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc. Natl. Acad. Sci. USA 89, 3055–3059.PubMedGoogle Scholar
  97. 97.
    Hung, A. Y., Haass, C., Nitsch, R. M., Qiu, W. Q., Citron, M., Wurtman, R. J., Growdon, J. H., and Selkoe, D. J. (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J. Biol. Chem. 268, 22,959–22,962.Google Scholar
  98. 98.
    Savage, M. J., Trusko, S. P., Howland, D. S., et al. (1998) Turnover of amyloid beta-protein in mouse brain and acute reduction of its level by phorbol ester. J. Neurosci. 18, 1743–1752.PubMedGoogle Scholar
  99. 99.
    Haring, R., Fisher, A., Marciano, D., Pittel, Z., Kloog, Y., Zuckerman, A., Eshhar, N., and Heldman, E. (1998) Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the ml muscarinic receptor to beta-amyloid precursor protein secretion. J. Neurochem. 71, 2094–2103.PubMedGoogle Scholar
  100. 100.
    Johnson-Wood, K., Lee, M., Motter, R., et al. (1997) Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 1550–1555.PubMedGoogle Scholar
  101. 101.
    Koo, E. H. and Squazzo, S. L. (1994) Evidence that production and release of amyloid b-protein involves the endocytic pathway. J. Biol. Chem. 269, 17,386–17,389.Google Scholar
  102. 102.
    Perez, R. G., Squazzo, S. L., and Koo, E. H. (1996) Enhanced release of amyloid beta-protein from codon 670/671 “Swedish” mutant beta-amyloid precursor protein occurs in both secretory and endocytic pathways. J. Biol. Chem. 271, 9100–9107.PubMedGoogle Scholar
  103. 103.
    Cataldo, A. M., Barnett, J. L., Pieroni, C., and Nixon, R. A. (1997) Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J. Neurosci. 17, 6142–6151.PubMedGoogle Scholar
  104. 104.
    Nixon, R. A., Cataldo, A. M., Paskevich, P. A., Hamilton, D. J., Wheelock, T. R., and Kanaley-Andrews, L. (1992) The lysosomal system in neurons. Involvement at multiple stages of Alzheimer’s disease pathogenesis. Ann. NY Acad. Sci. 674, 65–88.PubMedGoogle Scholar
  105. 105.
    Gouras, G. K., Tsai, J., Naslund, J., et al. (2000) Intraneuronal Ab42 accumulation in human brain. Am. J. Pathol. 156, 15–20.PubMedGoogle Scholar
  106. 106.
    D’Andrea, M. R., Nagele, R. G., Wang, H. Y., Peterson, P. A., and Lee, D. H. (2001) Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s disease. Histopathology 38, 120–134.PubMedGoogle Scholar
  107. 107.
    Soriano, S., Chyung, A. S., Chen, X., Stokin, G. B., Lee, V. M., and Koo, E. H. (1999) Expression of beta-amyloid precursor protein-CD3gamma chimeras to demonstrate the selective generation of amyloid beta(1–40) and amyloid beta(1–42) peptides within secretory and endocytic compartments. J. Biol. Chem. 274, 32,295–32,300.Google Scholar
  108. 108.
    Grant, S. M., Ducatenzeiler, A., Szyf, M., and Cuello, A. C. (2000) Aβ immunoreactive material is present in several intracellular compartments in transfected, neuronally differentiated, P19 cells expressing the human amyloid β-protein precursor. J. Alz. Dis. 2, 207–222.Google Scholar
  109. 109.
    Hartmann, T. (1999) Intracellular biology of Alzheimer’s disease amyloid beta peptide. Eur. Arch. Psychiatry Clin. Neurosci. 249, 291–298.PubMedGoogle Scholar
  110. 110.
    Cook, D. G., Forman, M. S., Sung, J. C., et al. (1997) Alzheimer’s A beta(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med. 3, 1021–1023.PubMedGoogle Scholar
  111. 111.
    Greenfield, J. P., Tsai, J., Gouras, G. K., et al. (1999) Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc. Natl. Acad. Sci. USA 96, 742–747.PubMedGoogle Scholar
  112. 112.
    Hartmann, T., Bieger, S. C., Bruhl, B., et al. (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nature Med. 3, 1016–1020.PubMedGoogle Scholar
  113. 113.
    Petanceska, S. S., Seeger, M., Checler, F., and Gandy, S. (2000) Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway. J. Neurochem. 74, 1878–1884.PubMedGoogle Scholar
  114. 114.
    Martin, B. L., Schrader-Fischer, G., Busciglio, J., Duke, M., Paganetti, P., and Yankner, B. A. (1995) Intracellular accumulation of beta-amyloid in cells expressing the Swedish mutant amyloid precursor protein. J. Biol. Chem. 270, 26,727–26,730.Google Scholar
  115. 115.
    Higaki, J., Quon, D., Zhong, Z., and Cordell, B. (1995) Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651–659.PubMedGoogle Scholar
  116. 116.
    Yamazaki, T., Selkoe, D. J., and Koo, E. H. (1995) Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J. Cell Biol. 129, 431–442.PubMedGoogle Scholar
  117. 117.
    Tienari, P. J., Ida, N., Ikonen, E., et al. (1997) Intracellular and secreted Alzheimer b-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 94, 4125–4130.PubMedGoogle Scholar
  118. 118.
    Haass, C., Hung, A. Y., Schlossmacher, M. G., et al. (1993) Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules. Ann. NY Acad. Sci. 695, 109–116.PubMedGoogle Scholar
  119. 119.
    Pike, C. J., Burdick, D., Walencewicz, A. J., Glabe, C. G., and Cotman, C. W. (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13, 1676–1687.PubMedGoogle Scholar
  120. 120.
    Lorenzo, A. and Yankner, B. A. (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA 91, 12,243–12,247.Google Scholar
  121. 121.
    Roher, A. E., Baudry, J., Chaney, M. O., Kuo, Y. M., Stine, W. B., and Emmerling, M. R. (2000) Oligomerizaiton and fibril assembly of the mayloid-beta protein. Biochim. Biophys. Acta. 1502, 31–43.PubMedGoogle Scholar
  122. 122.
    Skovronsky, D. M., Doms, R. W., and Lee, V. M. (1998) Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J. Cell Biol. 141, 1031–1039.PubMedGoogle Scholar
  123. 123.
    Lee, S. J., Liyanage, U., Bickel, P. E., Xia, W., Lansbury, P. T., Jr., and Kosik, K. S. (1998) A detergent-insoluble membrane compartment contains A beta in vivo. Nat. Med. 4, 730–734.PubMedGoogle Scholar
  124. 124.
    Mochizuki, A., Tamaoka, A., Shimohata, A., Komatsuzaki, Y., and Shoji, S. (2000) Abeta42 positive non-pyramidal neurons around amyloid plaques in Alzheimer’s disease. Lancet 355, 42–43.PubMedGoogle Scholar
  125. 125.
    Walsh, D. M., Klyubin, I., Fadeeva, J. V., et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539.PubMedGoogle Scholar
  126. 126.
    Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., and Neve, R. L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245, 417–420.PubMedGoogle Scholar
  127. 127.
    Yankner, B. A., Caceres, A., and Duffy, L. K. (1990) Nerve growth factor potentiates the neurotoxicity of beta amyloid. Proc. Natl. Acad. Sci. USA 87, 9020–9023.PubMedGoogle Scholar
  128. 128.
    Neve, R. L. and Robakis, N. K. (1998) Alzheimer’s disease: a re-examination of the amyloid hypothesis. Trends Neurosci. 21, 15–19.PubMedGoogle Scholar
  129. 129.
    Kowall, N. W., Beal, M. F., Busciglio, J., Duffy, L. K., and Yankner, B. A. (1991) An in vivo model for the neurodegenerative effects of b amyloid and protection by substance P. Proc. Natl. Acad. Sci. USA 88, 7247–7251.PubMedGoogle Scholar
  130. 130.
    Harkany, T., O’Mahony, S., Kelly, J. P., et al. (1998) Beta-amyloid(Phe(SO3H)24)25–35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation. Behav. Brain Res. 90, 133–145.PubMedGoogle Scholar
  131. 131.
    Geula, C., Wu, C. K., Saroff, D., Lorenzo, A., Yuan, M., and Yankner, B. A. (1998) Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat. Med. 4, 827–831.PubMedGoogle Scholar
  132. 132.
    Knauer, M. F., Soreghan, B., Burdick, D., Kosmoski, J., and Glabe, C. G. (1992) Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein. Proc. Natl. Acad. Sci. USA 89, 7437–7441.PubMedGoogle Scholar
  133. 133.
    Xia, W., Zhang, J., Ostaszewski, B. L., et al. (1998) Presenilin 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in endoplasmic reticulum and Golgi. Biochemistry 37, 16,465–16,471.Google Scholar
  134. 134.
    Chui, D. H., Tanahashi, H., Ozawa, K., et al. (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat. Med. 5, 560–564.PubMedGoogle Scholar
  135. 135.
    Wirths, O., Multhaup, G., Czech, C., Blanchard, V., et al. (2001) Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci. Lett. 306, 116–120.PubMedGoogle Scholar
  136. 136.
    Gyure, K. A., Durham, R., Stewart, W. F., Smialek, J. E., and Troncoso, J. C. (2001) Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch. Pathol. Lab. Med. 125, 489–492.PubMedGoogle Scholar
  137. 137.
    Yang, A. J., Knauer, M., Burdick, D. A., and Glabe, C. (1995) Intracellular A beta 1–42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J. Biol. Chem. 270, 14,786–14,792.Google Scholar
  138. 138.
    Burdick, D., Kosmoski, J., Knauer, M. F., and Glabe, C. G. (1997) Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer’s amyloid peptide, A beta 1–42, in differentiated PC12 cells. Brain Res. 746, 275–284.PubMedGoogle Scholar
  139. 139.
    Smith, M. A. and Perry, G. (1995) Free radical damage, iron, and Alzheimer’s disease. J. Neurol. Sci. 134 Suppl, 92–94.PubMedGoogle Scholar
  140. 140.
    Roher, A. E., Lowenson, J. D., Clarke, S., Woods, A. S., Cotter, R. J., Gowing, E., and Ball, M. J. (1993) Beta-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 10,836–10,840.Google Scholar
  141. 141.
    Bahr, B. A., Hoffman, K. B., Yang, A. J., Hess, U. S., Glabe, C. G., and lynch, G. (1998) Amyloid beta protein is internalized selectively by hippocampal field CA1 and causes neurons to accumulate amyloidogenic carboxyterminal fragments of the amyloid precursor protein. J. Comp Neurol. 397, 139–147.PubMedGoogle Scholar
  142. 142.
    Burdick, D., Soreghan, B., Kwon, M., et al. (1992) Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J. Biol. Chem. 267, 546–554.PubMedGoogle Scholar
  143. 143.
    Yang, A. J., Chandswangbhuvana, D., Shu, T., Henschen, A., and Glabe, C. G. (1999) Intracellular accumulation of insoluble, newly synthesized abetan-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J. Biol. Chem. 274, 20,650–20,656.Google Scholar
  144. 144.
    Cataldo, A. M., Thayer, C. Y., Bird, E. D., Wheelock, T. R., and Nixon, R. A. (1990) Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer’s disease: evidence for a neuronal origin. Brain Res. 513, 181–192.PubMedGoogle Scholar
  145. 145.
    Omar, R., Pappolla, M., Argani, I., and Davis, K. (1993) Acid phosphatase activity in senile plaques and cerebrospinal fluid of patients with Alzheimer’s disease. Arch. Pathol. Lab. Med. 117, 166–169.PubMedGoogle Scholar
  146. 146.
    Sze, C. I., Troncoso, J. C., Kawas, C., Mouton, P., Price, D. L., and Martin, L. J. (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J. Neuropathol. Exp. Neurol. 56, 933–944.PubMedGoogle Scholar
  147. 147.
    Masliah, E., Mallory, M., Hansen, L., DeTeresa, R., Alford, M., and Terry, R. (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci. Lett. 174, 67–72.PubMedGoogle Scholar
  148. 148.
    Koistinaho, M., Kettunen, M. I., Goldsteins, G., et al. (2002) Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc. Natl. Acad. Sci. USA 99, 1610–1615.PubMedGoogle Scholar
  149. 149.
    Tabira, T., Chui, D. H., and Kuroda, S. (2002) Significance of intracellular Abeta42 accumulation in Alzheimer’s disease. Front Biosci. 7, a44-a49.PubMedGoogle Scholar
  150. 150.
    LaFerla, F. M., Troncoso, J. C., Strickland, D. K., Kawas, C. H., and Jay, G. (1997) Neuronal cell death in Alzheimer’s disease correlates with apoE uptake and intracellular Abeta stabilization. J. Clin. Invest 100, 310–320.PubMedGoogle Scholar
  151. 151.
    Hsia, A. Y., Masliah, E., McConlogue, L., et al. (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233.PubMedGoogle Scholar
  152. 152.
    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, 1381–1388.PubMedGoogle Scholar
  153. 153.
    Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., and Crowther, R. A. (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526.PubMedGoogle Scholar
  154. 154.
    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, 4051–4055.PubMedGoogle Scholar
  155. 155.
    Otvos, L., Jr., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., and Lee, V. M. (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J. Neurosci. Res. 39, 669–673.PubMedGoogle Scholar
  156. 156.
    Crowther, T., Goedert, M., and Wischik, C. M. (1989) The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer’s disease. Ann. Med. 21, 127–132.PubMedGoogle Scholar
  157. 157.
    Crowther, R. A., Olesen, O. F., Jakes, R., and Goedert, M. (1992) The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer’s disease. FEBS Lett. 309, 199–202.PubMedGoogle Scholar
  158. 158.
    Crowther, R. A., Olesen, O. F., Smith, M. J., Jakes, R., and Goedert, M. (1994) Assembly of Alzheimer-like filaments from full-length tau protein. FEBS Lett. 337, 135–138.PubMedGoogle Scholar
  159. 159.
    Mandelkow, E. M. and Mandelkow, E. (1998) Tau in Alzheimer’s disease. Trends Cell Biol. 8, 425–427.PubMedGoogle Scholar
  160. 160.
    Iqbal, K., Alonso, A. D., Gondal, J. A., et al. (2000) Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach. J. Neural Transm. 59 Suppl, 213–222.Google Scholar
  161. 161.
    Dustin, P. and Flament-Durand, J. (1982) Disturbances of axoplasmic transport in Alzheimer’s disease, in Axoplasmic Transport and Pathology. (Weiss, D. G. and Gorio, A., eds.) Springer-Verlag, Berlin, pp. 131–136.Google Scholar
  162. 162.
    Grundke-Iqbal, I. and Iqbal, K. (1999) Tau pathology generated by overexpression of tau. Am. J. Pathol. 155, 1781–1785.PubMedGoogle Scholar
  163. 163.
    Mena, R., Wischik, C. M., Novak, M., Milstein, C., and Cuello, A. C. (1991) A progressive deposition of paired helical filaments (PHF) in the brain characterizes the evolution of dementia in Alzheimer’s disease. An immunocytochemical study with a monoclonal antibody against the PHF core. J. Neuropathol. Exp. Neurol. 50, 474–490.PubMedGoogle Scholar
  164. 164.
    Wischik, C. M., Harrington, C. R., Mukaetova-Ladinska, E. B., Novak, M., Edwards, P. C., and McArthur, F. K. (1992) Molecular characterization and measurement of Alzheimer’s disease pathology: implications for genetic and environmental aetiology. Ciba Found. Symp. 169, 268–293.PubMedGoogle Scholar
  165. 165.
    Holzer, M., Holzapfel, H.-P., Zedlick, D., Brückner, M. K., and Arendt, T. (1994) Abnormally phosphorylated tau protein in Alzheimer’s disease: Heterogeneity of individual regional distribution and relationship to clinical severity. Neuroscience 63, 499–516.PubMedGoogle Scholar
  166. 166.
    Trojanowski, J. Q. and Lee, V. M. (1994) Paired helical filament tau in Alzheimer’s disease. The kinase connection. Am. J. Pathol. 144, 449–453.PubMedGoogle Scholar
  167. 167.
    Jellinger, K. A. and Bancher, C. (1998) Senile dementia with tangles (tangle predominant form of senile dementia). Brain Pathol. 8, 367–376.PubMedGoogle Scholar
  168. 168.
    Gotz, J., Chen, F., van Dorpe, J., and Nitsch, R. M. (2001) Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495.PubMedGoogle Scholar
  169. 169.
    Lewis, J., Dickson, D. W., Lin, W. L., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491.PubMedGoogle Scholar
  170. 170.
    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, 95–130.PubMedGoogle Scholar
  171. 171.
    Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P., and Anderton, B. H. (1992) Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58–62.PubMedGoogle Scholar
  172. 172.
    Tomidokoro, Y., Harigaya, Y., Matsubara, E., et al. (2001) Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J. Pathol. 194, 500–506.PubMedGoogle Scholar
  173. 173.
    Takahashi, M., Tomizawa, K., Sato, K., Ohtake, A., and Omori, A. (1995) A novel tau-tubulin kinase from bovine brain. FEBS Lett. 372, 59–64.PubMedGoogle Scholar
  174. 174.
    Drewes, G., Lichtenberg-Kraag, B., Doring, F., et al. (1992) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 11, 2131–2138.PubMedGoogle Scholar
  175. 175.
    Liu, W. K., Williams, R. T., Hall, F. L., Dickson, D. W., and Yen, S. H. (1995) Detection of a Cdc2-related kinase associated with Alzheimer paired helical filaments. Am. J. Pathol. 146, 228–238.PubMedGoogle Scholar
  176. 176.
    Drewes, G., Ebneth, A., Preuss, U., et al. (1997) A novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297–308.PubMedGoogle Scholar
  177. 177.
    Johnson, G. V. (1992) Differential phosphorylation of tau by cyclic AMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase II: metabolic and functional consequences. J. Neurochem. 59, 2056–2062.PubMedGoogle Scholar
  178. 178.
    Litersky, J. M. & Johnson, G. V. (1992) Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J. Biol. Chem. 267, 1563–1568.PubMedGoogle Scholar
  179. 179.
    Greenwood, J. A., Scott, C. W., Spreen, R. C., Caputo, C. B., and Johnson, G. V. (1994) Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor. J. Biol. Chem. 269, 4373–4380.PubMedGoogle Scholar
  180. 180.
    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, 3563–3571.PubMedGoogle Scholar
  181. 181.
    Reynolds, C. H., Utton, M. A., Gibb, G. M., Yates, A., and Anderton, B. H. (1997) Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein J. Neurochem. 68, 1736–1744.PubMedGoogle Scholar
  182. 182.
    Imahori, K., Hoshi, M., Ishiguro, K., et al. (1998) Possible role of tau protein kinases in pathogenesis of Alzheimer’s disease. Neurobiol. Aging 19, S93-S98.PubMedGoogle Scholar
  183. 183.
    Augustinack, J. C., Schneider, A., Mandelkow, E. M., and Hyman, B. T. (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta. Neuropathol. (Berl.) 103, 26–35.Google Scholar
  184. 184.
    Perry, G., Roder, H., Nunomura, A., et al. (1999) Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. NeuroReport 10, 2411–2415.PubMedGoogle Scholar
  185. 185.
    Knowles, R. B., Chin, J., Ruff, C. T., and Hyman, B. T. (1999) Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: implications for MAP kinase activation in Alzheimer disease. J. Neuropathol. Exp. Neurol. 58, 1090–1098.PubMedCrossRefGoogle Scholar
  186. 186.
    Ferrer, I., Blanco, R., Carmona, M., and Puig, B. (2001) 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, 1397–1415.PubMedGoogle Scholar
  187. 187.
    Greenberg, S. M., Koo, E. H., Selkoe, D. J., Qiu, W. Q., and Kosik, K. S. (1994) Secreted β-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. Proc. Natl. Acad. Sci. USA 91, 7104–7108.PubMedGoogle Scholar
  188. 188.
    Grant, S. M., Shankar, S. L., Chalmers-Redman, R. M. E., Tatton, W. G., Szyf, M., and Cuello, A. C. (1999) Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). NeuroReport 10, 41–46.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  1. 1.Department of Pharmacology and TherapeuticsMcGill UniversityMontrealCanada

Personalised recommendations