The β-Amyloid Model of Alzheimer’s Disease

Conformation Change, Receptor Cross-Linking, and the Initiation of Apoptosis
  • Carl W. Cotman
  • David H. Cribbs
  • Aileen J. Anderson
Part of the Contemporary Neuroscience book series (CNEURO)


In 1855, Virchow, looking for a link between plants and animals, discovered deposits of a substance in the brain that stained with iodine; he named this substance amyloid, after the Greek word for starch (1). The amyloid in these deposits was later identified as a peptide, and subsequently recognized as the major component of senile plaques in Alzheimer’s disease (AD). β-Amyloid (Aβ) has been used extensively to identify AD pathology. It was generally thought that Aβ itself was metabolically inert, lacking in biological activity, until recent studies with cultured neurons and other cells provided the first clear evidence that Aβ is an active peptide. Aβ has been shown to initiate neuronal degeneration and transiently enhance neuronal growth. These observations opened up the action of Aβ to extensive investigation and led to the key finding that the biological activity of Aβ is dependent on its transformation into a β-sheet conformation and related higher order molecular assemblies. This is of fundamental importance, because it suggests that the biological activity of Aβ is dependent on protein conformation and that the transition into this conformation generates a new biological activity. Indeed, the amount of Aβ that accumulates in the brain appears to correlate to the decline of brain function (2). The consequences of such a relationship between biological activity and protein conformation are critical to understanding the role of Aß and other β-pleated sheet protein assemblies, such as prion protein, in disease.


Prion Protein Terminal Deoxynucleotidyl Transferase Postmortem Delay Initiate Cell Death Receptor Crosslinking 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Virchow, R. (1855) Zur Cellulose-Fruge, VirchowsArch. 8, 140–144.CrossRefGoogle Scholar
  2. 2.
    Cummings, B. J. and Cotman, C. W. (1995) Image analysis of beta-amyloid load in Alzheimer’s disease and relation to dementia severity, Lancet 346, 1524–1528.PubMedCrossRefGoogle Scholar
  3. 3.
    Whitson, J. S., Selkoe, D. J., and Cotman, C. W. (1989) Amyloid beta protein enhances the survival of hippocampal neurons in vitro, Science 243, 1488–1490.PubMedCrossRefGoogle Scholar
  4. 4.
    Yankner, B. A., Duffy, L. K., and Kirschner, D. A. (1990) Neurotrophic and neurotoxic effects of amyloid 3-protein: reversal by tachykinin neuropeptides, Science 250, 279–282.PubMedCrossRefGoogle Scholar
  5. 5.
    Koh, J. Y., Yang, L. L., and Cotman, C. W. (1990) J3-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage, Brain Res. 533, 315–320.PubMedCrossRefGoogle Scholar
  6. 6.
    Yankner, B. A., Dawes, L. R., Fisher, S., Villa, K. L., Oster, G. M. L., and Neve, R. L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease, Science 245, 417–420.PubMedCrossRefGoogle Scholar
  7. 7.
    Pike, C. J., Walencewicz, A. J., Glabe, C. G., and Cotman, C. W. (1991) In vitro aging of ß-amyloid protein causes peptide aggregation and neurotoxicity, Brain Res. 563, 311–314.Google Scholar
  8. 8.
    Pike, C. J., Walencewicz, A. J., Glabe, C. G., and Cotman, C. W. (1991) Aggregation-related toxicity of synthetic ß-amyloid protein in hippocampal cultures, Eur. J. Pharmacol. 207, 367, 368.Google Scholar
  9. 9.
    Behl, C., Davis, J., Cole, G. M., and Schubert, D. (1992) Vitamin E protects nerve cells from amyloid beta protein toxicity, Biochem. Biophys. Res. Commun. 186, 944–950.PubMedCrossRefGoogle Scholar
  10. 10.
    Takadera, T., Sakura, N., Mohri, T., and Hashimoto, T. (1993) Toxic effect of a beta-amyloid peptide (beta 22–35) on the hippocampal neuron and its prevention, Neurosci. Lett. 161, 41–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Busciglio, J., Gabuzda, D. H., Matsudaira, P., and Yankner, B. A. (1993) Generation of betaamyloid in the secretory pathway in neuronal and nonneuronal cells, Proc. Natl. Acad. Sci. USA 90, 2092–2096.PubMedCrossRefGoogle Scholar
  12. 12.
    Mattson, M. P., Tomaselli, K. J., and Rydel, R. E. (1993) Calcium-destabilizing and neurodegenerative effects of aggregated ß-amyloid peptide are attenuated by basic FGF, Brain Res. 621, 35–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Pike, C. J., Burdick, D., Walencewicz, A., Glabe, C. G., and Cotman, C. W. (1993) Neurodegeneration induced by ß-amyloid peptides in vitro: the role of peptide assembly state, J. Neurosci. 13, 1676–1687.Google Scholar
  14. 14.
    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/ß-amyloid peptide analogs, J. Biol. Chem. 267, 546–554.PubMedGoogle Scholar
  15. 15.
    Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C. L., and Beyreuther, K. (1991) Aggregation and secondary structure of synthetic amyloid ßA4 peptides of Alzheimer’s disease, J. Mol. Biol. 218, 149–163.PubMedCrossRefGoogle Scholar
  16. 16.
    Pike, C. J., Cummings, B. J., and Cotman, C W. (1992) ß-amyloid induces neuritic dystrophy in vitro: similarities with Alzheimer pathology, Neuroreport 3, 769–772.PubMedCrossRefGoogle Scholar
  17. 17.
    Loo, D. T., Copani, A. G., Pike, C. J., Whittemore, E. R., Walencewicz, A. J., and Cotman, C. W. (1993) Apoptosis is induced by beta-amyloid in cultured central nervous system neurons, Proc. Natl. Acad. Sci. USA 90, 7951–7955.PubMedCrossRefGoogle Scholar
  18. 18.
    Watt, J., Pike, C. J., Walencewicz, A. J., and Cotman, C. W. (1994) Ultrastructural analysis of ß-amyloid-induced apoptosis in cultured hippocampal neurons, Brain Res. 661, 147–156.PubMedCrossRefGoogle Scholar
  19. 19.
    Wyllie, A. H., Kerr, J. F. R., and Currie, A. R. (1980) Cell death: the significance of apoptosis, Int. Rev. Cytol. 68, 251–306.PubMedCrossRefGoogle Scholar
  20. 20.
    Forloni, G., Chiesa, R., Smiroldo, S., Verga, L., Salmona, M., Tagliavini, F., and Angeretti, N. (1993) Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35, Neuroreport 4, 523–526.PubMedCrossRefGoogle Scholar
  21. 21.
    Frautschy, S. A., Baird, A., and Cole, G. M. (1991) Effects of injected Alzheimer betaamyloid cores in rat brain, Proc. Natl. Acad. Sci. USA 88, 8362–8366.PubMedCrossRefGoogle Scholar
  22. 22.
    Emre, M., Geula, C., Ransil, B. J., and Mesulam, M. M. (1992) The acute neurotoxicity and effects upon cholinergic axons of intracerebrally injected beta-amyloid in the rat brain, Neurobiol. Aging 13, 553–559.PubMedCrossRefGoogle Scholar
  23. 23.
    Kowall, N. W., McKee, A. C., Yankner, B. A., and Beal, M. F. (1992) In vivo neurotoxicity of beta-amyloid [beta(1–40)] and the beta(25–35) fragment, Neurobiol. Aging 13, 537–542.Google Scholar
  24. 24.
    Pike, C. J., Overman, M. J., and Cotman, C. W. (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro, J. Biol. Chem. 270, 23,895–23, 898.Google Scholar
  25. 25.
    Forloni, G., Angeretti, N., Chiesa, R., Monzani, E., Salmona, M., Bugiani, O., and Tagliavini, F. (1993) Neurotoxicity of a prion protein fragment, Nature 362, 543–546.PubMedCrossRefGoogle Scholar
  26. 26.
    Selvaggini, C., De, G. L., Cantu, L., Ghibaudi, E., Diomede, L., Passerini, F., Forloni, G., Bugiani, O., Tagliavini, F., and Salmona, M. (1993) Molecular characteristics of a protease-resistant, amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein, Biochem. Biophys. Res. Commun. 194, 1380–1386.PubMedCrossRefGoogle Scholar
  27. 27.
    Tagliavini, F., Prelli, F., Verga, L., Giaccone, G., Sarma, R., Gorevic, P., Ghetti, B., Passerini, F., Ghibaudi, E., Forloni, G., Schmona, M., Bugiani, O., and Frangione, B. (1993) Synthetic peptides homologous to prion protein residues 106–147 form amyloid-like fibrils in vitro, Proc. Natl. Acad. Sci. USA 90, 9678–9682.PubMedCrossRefGoogle Scholar
  28. 28.
    De Gioia, L., Selvaggini, C., Ghibaudi, E., Diomede, L., Bugiani, O., Forloni, G., Tagliavini, F., and Salmona, M. (1994) Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein, J. Biol. Chem. 269, 7859–7862.PubMedGoogle Scholar
  29. 29.
    May, P. C., Boggs, L. N., and Fuson, K. S. (1993) Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer’s disease amyloid-ß neurotoxicity, J. Neurochem. 61, 2330–2333.PubMedCrossRefGoogle Scholar
  30. 30.
    Lorenzo, A., Razzaboni, B., Weir, G. C., and Yankner, B. A. (1994) Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus, Nature 368, 756–760.PubMedCrossRefGoogle Scholar
  31. 31.
    Monaghan, D. T., Bridges, R. J., and Cotman, C. W. (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system, Ann. Rev. Pharmacol. Toxicol. 29, 365–102.CrossRefGoogle Scholar
  32. 32.
    Cribbs, D. H., Pike, C. J., Weinstein, S. L., Velazquez, P., and Cotman, C. W. (1996) All-Denantiomers of ß-amyloid exhibit similar biological properties to all-L-ß-amyloids (submitted).Google Scholar
  33. 33.
    Pike, C. J., Walencewicz-Wasserman, A. J., Kosmoski, J., Cribbs, D. H., Glabe, C. G., and Cotman, C. W. (1995) Structure—activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity, J. Neurochem. 64, 253–265.PubMedCrossRefGoogle Scholar
  34. 34.
    Simmons, L. K., May, P. C., Tomaselli, K. J., Rydel, R. E., Fuson, K. S., Brigham, E. F., Wright, S., Lieberburg, I., Becker, G. W., Brems, D. N., and Li, W. Y. (1994) Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro, Mol. Pharmacol. 45, 373–379.PubMedGoogle Scholar
  35. 35.
    Howlett, D. R., Jennings, K. H., Lee, D. C., Clark, M. S., Brown, F., Wetzel, R., Wood, S. J., Camilleri, P., and Roberts, G. W. (1995) Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide, Neurodegeneration 4, 23–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Raff, M. C., Barres, B. A., Burne, J. F., Coles, H. S., Ishizaki, Y., and Jacobson, M. D. (1993) Programmed cell death and the control of cell survival: lessons from the nervous system, Science 262, 695–700.PubMedCrossRefGoogle Scholar
  37. 37.
    Dellabona, P., Peccoud, J., Kappler, J., Marrack, P., Benoist, C., and Mathis, D. (1990) Superantigens interact with MHC class II molecules outside of the antigen groove, Cell 62, 1115–1121.PubMedCrossRefGoogle Scholar
  38. 38.
    Marrack, P. and Kappler, J. (1990) The staphylococcal enterotoxins and their relatives (published erratum appears in Science 1990 Jun 1, 248[4959]:1066) (see comments), Science 248, 705–711.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagata, S. and Golstein, P. (1995) The Fas death factor, Science 267, 1449–1456.PubMedCrossRefGoogle Scholar
  40. 40.
    Ruoslahti, E. and Reed, J. C. (1994) Anchorage dependence, integrins, and apoptosis, Cell 77, 477, 478.Google Scholar
  41. 41.
    Shi, Y. F., Sahai, B. M., and Green, D. R. (1989) Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes, Nature 339, 625, 626.Google Scholar
  42. 42.
    Lenardo, M. J. (1991) Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis, Nature 353, 858–861.PubMedCrossRefGoogle Scholar
  43. 43.
    Radvanyi, L. G., Mills, G. B., and Miller, R. G. (1993) Religation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death, J. Immunol. 150, 5704–5715.PubMedGoogle Scholar
  44. 44.
    Banda, N. K., Bernier, J., Kurahara, D. K., Kurrie, R., Haigwood, N., Sekaly, R.-P., and Finkel, T. H. (1992) Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis, J. Exp. Med. 176, 1099–1106.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith, C. A., Williams, G. T., Kingston, R., Jenkinson, E. J., and Owen, J. J. (1989) Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures, Nature 337, 181–184.PubMedCrossRefGoogle Scholar
  46. 46.
    Takahashi, S., Maecker, H. T., and Levy, R. (1989) DNA fragmentation and cell death mediated by T cell antigen receptor/CD3 complex on a leukemia T cell line, Eur. J. Immunol. 19, 1911–1919.PubMedCrossRefGoogle Scholar
  47. 47.
    Cotman, C. W. and Anderson, A. J. (1995) A potential role for apoptosis in neurodegeneration and Alzheimer’s disease, Mol. Neurobiol. 10, 19–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Cotman, C. W. and Taylor, D. (1974) Localization and characterization of concanavalin A receptors in the synaptic cleft, J. Cell Biol. 62, 236–242.PubMedCrossRefGoogle Scholar
  49. 49.
    Cribbs, D. H., Kreng, V. M., Anderson, A. J., and Cotman, C. W. (1996) Crosslinking of membrane glycoproteins by Concanavalin A induces apoptosis in cortical neurons, Neuroscience,in press.Google Scholar
  50. 50.
    Kang, S. M., Beverly, B., Tran, A. C., Brorson, K., Schwartz, R. H., and Lenardo, M. J. (1992) Transactivation by AP-1 is a molecular target of T cell clonal anergy, Science 257, 1134–1138.PubMedCrossRefGoogle Scholar
  51. 51.
    Busciglio, J., Lorenzo, A., andYankner, B. A. (1992) Methodological variables in the assessment of beta amyloid neurotoxicity, Neurobiol. Aging 13, 609–612.PubMedCrossRefGoogle Scholar
  52. 52.
    Davis-Salinas, J., Saporito-Irwin, S. M., Cotman, C. W., and Van Nostrand, W. E. (1995) Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells, J. Neurochem. 65, 931–934.PubMedCrossRefGoogle Scholar
  53. 53.
    Pike, C. J., Cummings, B. J., Monzavi, R., and Cotman, C. W. (1994) Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer’s disease, Neuroscience 63, 517–531.PubMedCrossRefGoogle Scholar
  54. 54.
    Fraser, P. E., Levesque, L., and McLachlan, D. R. (1994) Alzheimer Aß amyloid forms an inhibitory neuronal substrate, J Neurochem. 62, 1227–1230.PubMedCrossRefGoogle Scholar
  55. 55.
    Haxby, J. V. and Rapoport, S. I. (1986) Abnormalities of regional brain metabolism in Alzheimer’s disease and their relation to functional impairment, Prog. Neuropsychopharmacol. Biol. Psychiatry 10, 427–438.PubMedCrossRefGoogle Scholar
  56. 56.
    McGeer, P. L., Kamo, H., Harrop, R., Li, D. K., Tuokko, H., McGeer, E. G., Adam, M. J., Ammann, W., Beattie, B. L., Calne, D. B., Martin, W. R. W., Pate, B. D., Rogers, J. G., Ruth, T. J., Sayre, C. I., and Stoessl, A. J. (1986) Positron emission tomography in patients with clinically diagnosed Alzheimer’s disease, Can. Med. Assoc. J. 134, 597–607.Google Scholar
  57. 57.
    Hoyer, S., Oesterreich, K., and Wagner, O. (1988) Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol. 235, 143–148.PubMedCrossRefGoogle Scholar
  58. 58.
    Beal, M. F., Hyman, B. T., and Koroshetz, W. (1993) Do deficits in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? TINS 16, 178–184.Google Scholar
  59. 59.
    Goto, I., Taniwaki, T., Hosokawa, S., Otsuka, M., Ichiya,Y., and Ichimiya,A. (1993) Positron emission tomographic (PET) studies in dementia, J. Neurol. Sci. 114, 1–6.Google Scholar
  60. 60.
    Copani, A., Koh, J., and Cotman, C. W. (1991) f3-amyloid increases neuronal susceptibility to injury by glucose deprivation, Neuroreport 2, 763–765.Google Scholar
  61. 61.
    Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberberg, I., and Rydel, R. E. (1992) 0.-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity, J. Neurosci. 12, 376–389.Google Scholar
  62. 62.
    Dornan, W. A., Kang, D. E., McCampbell, A., and Kang, E. E. (1993) Bilateral injections of ßA(25–35)+IBO into the hippocampus disrupts acquisition of spatial learning in the rat, NeuroReport 5, 165–168.PubMedCrossRefGoogle Scholar
  63. 63.
    LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C., and Jay, G. (1995) The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in trans-genic mice, Nature Genet. 9, 21–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Duke, R. C., Chervenak, R., and Cohen, J. J. (1983) Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis, Proc. Natl. Acad. Sci. USA 80, 6361–6365.PubMedCrossRefGoogle Scholar
  65. 65.
    Wyllie, A. H., Morris, R. G., Smith, A. L., and Dunlop, D. (1984) Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macro-molecular synthesis, J. Pathol. 142, 67–77.PubMedCrossRefGoogle Scholar
  66. 66.
    Tepper, C. G. and Studzinski, G. R. (1992) Teniposide induces nuclear but not mitochondrial DNA degradation, Cancer Res. 52, 3384–3390.PubMedGoogle Scholar
  67. 67.
    Zakeri, Z. F., Quaglino, D., Latham, T., and Lockshin, R. A. (1993) Delayed internucleosomal DNA fragmentation in programmed cell death, FASEB J. 7, 470–478.PubMedGoogle Scholar
  68. 68.
    Lennon, S. V., Martin, S. J., and Cotter, T. G. (1991) Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli, Cell Proliferation 24, 203–214.PubMedCrossRefGoogle Scholar
  69. 69.
    Kunimoto, M. (1994) Methylmercury induces apoptosis of rat cerebellar neurons in primary culture, Biochem. Biophys. Res. Commun. 204, 310–317.PubMedCrossRefGoogle Scholar
  70. 70.
    Su, J. H., Anderson, A. J., Cummings, B. J., and Cotman, C. W. (1994) Immunohistochemical evidence for DNA fragmentation in neurons in the AD brain, Neuroreport 5, 2529–2533.PubMedCrossRefGoogle Scholar
  71. 71.
    Anderson, A. J., Su, J. H., and Cotman, C. W. (1996) DNA damage and apoptosis in Alzheimer’s disease: colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay, J. Neurosci. 16, 1710–1719.PubMedGoogle Scholar
  72. 72.
    Mullaart, E., Boerrigter, M. E. T. I., 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, 169–173.PubMedCrossRefGoogle Scholar
  73. 73.
    Satou, T., Cummings, B. J., and Cotman, C. W. (1995) Immunoreactivity for BCL-2 protein within neurons in the Alzheimer’s disease brain increases with disease severity, Brain Res. 697, 35–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Su, J. H., Satou, T., Anderson, A. J., and Cotman, C. W. (1996) Up-regulation of Bc1–2 is associated with neuronal DNA damage in Alzheimer’s disease, Neuroreport 7, 437–440.PubMedCrossRefGoogle Scholar
  75. 75.
    Yamazaki, T., Yamaguchi, H., Nakazato, Y., Ishiguro, K., Kawarabayashi, T., and Hirai, S. (1992) Ultrastructural characterization of cerebellar diffuse plaques in Alzheimer’s disease, J. Neuropathol. Exp. Neurol. 51, 281–286.PubMedCrossRefGoogle Scholar
  76. 76.
    Li, Y. T., Woodruff, P. D., and Trojanowski, J. Q. (1994) Amyloid plaques in cerebellar cortex and the integrity of Purkinje cell dendrites, Neurobiol. Aging 15, 1–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Colotta, F., Polentarutti, N., Sironi, M., and Mantovani, A. (1992) Expression and involvement of c-fos and c-Jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines, J. Biol. Chem. 267, 18,278–18, 283.Google Scholar
  78. 78.
    Estus, S., Zaks, W. J., Freeman, R. S., Gruda, M., Bravo, R., and Johnson, E. M. (1994) Altered gene expression in neurons during programmed cell death: identification of c-Jun as necessary for neuronal apoptosis, J. Cell Biol. 126, 1717–1727.CrossRefGoogle Scholar
  79. 79.
    Ham, J., Babij, C., Whitfield, J., Pfarr, C. M., Lallemand, D., Yaniv, M., and Rubin, L. L. (1995) A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death, Neuron 14, 927–939.PubMedCrossRefGoogle Scholar
  80. 80.
    Spillane, J. A., White, P., Goodhardt, M. J., Flack, R. H. A., Bowen, D. M., and Davison, A. N. (1977) Selective vulnerability of neurones in organic dementia, Nature 266, 558–559.PubMedCrossRefGoogle Scholar
  81. 81.
    Rossor, M. N., Garrett, N. J., Johnson, A. L., Mountjoy, C. Q., Roth, M., and Iverson, L. L. (1982) A post-mortem study of the cholinergic and GABA systems in senile dementia, Brain 105, 313–330.PubMedCrossRefGoogle Scholar
  82. 82.
    Smith, C. C., Bowen, D. M., Sims, N. R., Neary, D., and Davison, A. N. (1983) Amino acid release from biopsy samples of temporal neocortex from patients with Alzheimer’s disease, Brain Res. 264, 138–141.PubMedCrossRefGoogle Scholar
  83. 83.
    Mountjoy, C. Q., Rossor, M. N., Iversen, L. L., and Roth, M. (1984) Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia, Brain 107, 507–518.PubMedCrossRefGoogle Scholar
  84. 84.
    Lowe, S. L., Francis, P. T., Procter, A. W., Palmer, A. M., Davison, A. N., and Bowen, D. M. (1988) Gamma-aminobutyric acid concentration in brain tissue at two stages ofAlzheimer’s disease, Brain 111, 785–799.PubMedCrossRefGoogle Scholar
  85. 85.
    Anderson, A. J., Pike, C. J., and Cotman, C. W. (1995) Differential induction of immediate early gene proteins in cultured neurons by beta-amyloid (A13): association of c-Jun with Aß-induced apoptosis, J. Neurochem. 65, 1487–1498.PubMedCrossRefGoogle Scholar
  86. 86.
    Anderson, A. J., Cummings, B. J., and Cotman, C. W. (1994) Increased immunoreactivity for Jun-and Fos-related proteins in Alzheimer’s disease: association with pathology, Exp. Neurol. 125, 286–295.PubMedCrossRefGoogle Scholar
  87. 87.
    Rosl, F. (1992) A simple and rapid method for detection of apoptosis in human cells, Nucleic Acids Res. 20, 5243.PubMedCrossRefGoogle Scholar
  88. 88.
    Tilly, J. L. and Hsueh, A. J. (1993) Microscale autoradiographic method for the qualitative and quantitative analysis of apoptotic DNA fragmentation, J. Cell. Physiol. 154, 519–526.PubMedCrossRefGoogle Scholar
  89. 89.
    Beilharz, E. J., Williams, C. E., Dragunow, M., Sirimanne, E. S., and Gluckman, P. D. (1995) Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss, Brain. Res. Mol. Brain. Res. 29, 1–14.PubMedCrossRefGoogle Scholar
  90. 90.
    Portera-Cailliau, C., Herdeen, J. C., Price, D. L., and Koliatsos, V. E. (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models, J. Neurosci. 15, 3775–3787.PubMedGoogle Scholar
  91. 91.
    Lippa, C. F., Hamos, J. E., Pulaski, S. D., DeGennaro, L. J., and Drachman, D. A. (1992) Alzheimer’s disease and aging: effects on perforant pathway perikarya and synapses, Neurobiol. Aging 13, 405–411.PubMedCrossRefGoogle Scholar
  92. 92.
    Boerrigter, M. E., Wei, J. Y., and Vijg, J. (1992) DNA repair and Alzheimer’s disease, J. Gerontol. 47, B 177–184.Google Scholar
  93. 93.
    Mazzarello, P., Poloni, M., Spadari, S., and Focher, F. (1992) DNA repair mechanisms in neurological diseases: facts and hypotheses, J Neurol. Sci. 112, 4–14.PubMedCrossRefGoogle Scholar
  94. 94.
    Cribbs, D. H., Martinou, J. C., Knowles, J., and Cotman, C. W. (1996) Overexpression of bc1–2 protects against ß-amyloid toxicity in cultured hippocampal neurons (submitted).Google Scholar
  95. 95.
    Reed, J. C. (1994) Bc1–2 and the regulation of programmed cell death, J. Cell Biol. 124, 1–6PubMedCrossRefGoogle Scholar
  96. 95a.
    Anderson, A. J., Su, J. H., and Cotman, C. W. (1996) Increase in immunoreactivity for the DNA repair enzyme Ref-1 in Alzheimer’s disease brain, submitted.Google Scholar
  97. 96.
    Xanthoudakis, S., Miao, G., Wang, F., Pan, Y., and Curran, T. (1992) Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme, EMBO J. 11 (9), 3323–3335.PubMedGoogle Scholar
  98. 97.
    Whittemore, E. R., Loo, D. T., and Cotman, C. W. (1994) Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons, Neuroreport 5, 1485–1488.PubMedCrossRefGoogle Scholar
  99. 98.
    Cribbs, D. H., Davis-Salinas, J., Cotman, C. W., and vanNostrand, W. E. (1995) ß-Amyloid induces increased expression and processing of the amyloid precursor proteinin cortical neurons, Alzheimer’s Res. 1, 197–200.Google Scholar
  100. 99.
    Wetzel, R. (1994) Mutations and off-pathway aggregation of proteins, Trends Biotechnol. 12, 193–198.PubMedCrossRefGoogle Scholar
  101. 100.
    Kelly, J. W. (1996) Alternative conformations of amyloidogenic proteins govern their behavior, Curr. Opinion Struct. Biol. 6, 11–17.CrossRefGoogle Scholar
  102. 101.
    Taubes, G. (1996) Misfolding the way to disease, Science 271, 1493–1495.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Carl W. Cotman
  • David H. Cribbs
  • Aileen J. Anderson

There are no affiliations available

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