Overview of the Alzheimer's Disease Pathology and Potential Therapeutic Targets

  • A. Claudio Cuello

This chapter succinctly summarizes some basic aspects of Alzheimer’s disease (AD) pathology for the nonexpert reader. The objective is to provide an overview for subsequent chapters that deal with specific current and prospective AD therapeutics. The AD literature is so vast that, unavoidably, it was not possible to cover all aspects of the interesting or exciting issues under investigation. Although this chapter reflects a personal view of the field, I have tried, as much as possible, to bring ideas that have the greatest consensus to the forefront.


Nerve Growth Factor Mild Cognitive Impairment Alzheimer Disease Potential Therapeutic Target Paired Helical Filament 
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  1. Allinson, T. M., Parkin, E. T., Turner, A. J., & Hooper, N. M. (2003). ADAMs family members as amyloid precursor protein alpha-secretases. Journal of Neuroscience Research, 74, 342–352.CrossRefPubMedGoogle Scholar
  2. Alzheimer, A., Stelzmann, R. A., Schnitzlein, H. N., & Murtagh, F. R. (1995). An English translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clinical Anatomy, 8, 429–431.CrossRefPubMedGoogle Scholar
  3. Andreasen, N., & Blennow, K. (2005). CSF biomarkers for mild cognitive impairment and early Alzheimer's disease. Clinical Neurology and Neurosurgery, 107, 165–173.CrossRefPubMedGoogle Scholar
  4. Archer, H. A., Edison, P., Brooks, D. J., Barnes, J., Frost, C., Yeatman, T., et al. (2006). Amyloid load and cerebral atrophy in Alzheimer's disease: An 11C-PIB positron emission tomography study. Annals of Neurology, 60, 145–147.CrossRefPubMedGoogle Scholar
  5. Bartus, R. T., Dean, R. L., III, Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408–414.CrossRefPubMedGoogle Scholar
  6. Bell, K. F. S., Bennett, D. A., & Cuello, A. C. (2007). Paradoxical cortical upregulation of glutamatergic synapses in Mild Cognitive Impairment, followed by progressive depletion and neuritic dystrophy in Alzheimer's disease. Submitted.Google Scholar
  7. Bell, K. F., & Cuello, A. C. (2006). Altered synaptic function in Alzheimer's disease. European Journal of Pharmacology, 545, 11–21.CrossRefPubMedGoogle Scholar
  8. Bell, K. F., Ducatenzeiler, A., Ribeiro-da-Silva, A., Duff, K., Bennett, D. A., & Cuello, A. C. (2006). The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiology of Aging, 27, 1644–1657.CrossRefPubMedGoogle Scholar
  9. Bell, K. F. S., Zheng, L., Fahrenholz, F., & Cuello, A. C. (2007). ADAM-10 over-expression increases cortical synaptogenesis. Neurobiological Aging, in press.Google Scholar
  10. Bennett, D. A. (2004). Mild cognitive impairment. Clinics in Geriatric Medicine, 20, 15–25.CrossRefPubMedGoogle Scholar
  11. Bertram, L., & Tanzi, R. E. (2004). The current status of Alzheimer's disease genetics: What do we tell the patients? Pharmacological Research, 50, 385–396.CrossRefPubMedGoogle Scholar
  12. Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005). Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron, 45, 675–688.CrossRefPubMedGoogle Scholar
  13. Birkenhager, W. H., & Staessen, J. A. (2006). Progress in cardiovascular diseases: Cognitive function in essential hypertension. Progress in Cardiovascular Diseases, 49, 1–10.CrossRefPubMedGoogle Scholar
  14. Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., 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.CrossRefPubMedGoogle Scholar
  15. Bowen, D. M., Smith, C. B., White, P., Davison, A. N. (1970). Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. BRAIN, 99, 459–496.CrossRefGoogle Scholar
  16. Braak, H., & Braak, E. (1998). Argyrophilic grain disease: Frequency of occurrence in different age categories and neuropathological diagnostic criteria. Journal of Neural Transmission, 105, 801–819.CrossRefPubMedGoogle Scholar
  17. Brayne, C., & Calloway, P. (1988). Normal ageing, impaired cognitive function, and senile dementia of the Alzheimer's type: A continuum? Lancet, 1, 1265–1267.CrossRefPubMedGoogle Scholar
  18. Briones, T. L. (2006). Environment, physical activity, and neurogenesis: Implications for prevention and treatment of Alzhemier's disease. Current Alzheimer Research, 3, 49–54.CrossRefPubMedGoogle Scholar
  19. Bruno, M. A., & Cuello, A. C. (2006). Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proceedings of the National Academy of Sciences of the United States of America, 103, 6735–6740.CrossRefPubMedGoogle Scholar
  20. Bruno, M. A., Ravid, R., & Cuello, A. C. (2006). Altered proNGF maturation and NGF degradation and the vulnerability of forebrain cholinergic neurons in Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 2[3], S476.Google Scholar
  21. Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., et al. (2006). M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron, 49, 671–682.CrossRefPubMedGoogle Scholar
  22. Cai, X. D., Golde, T. E., & Younkin, S. G. (1993). Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science, 259, 514–516.CrossRefPubMedGoogle Scholar
  23. Chan, D., Janssen, J. C., Whitwell, J. L., Watt, H. C., Jenkins, R., Frost, C., et al. (2003). Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: Longitudinal MRI study. Lancet, 362, 1121–1122.CrossRefPubMedGoogle Scholar
  24. Chertkow, H. (2002). Mild cognitive impairment. Current Opinion in Neurology, 15, 401–407.CrossRefPubMedGoogle Scholar
  25. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., et al. (1992). Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature, 360, 672–674.CrossRefPubMedGoogle Scholar
  26. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., 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 Medicine, 3, 67–72.CrossRefPubMedGoogle Scholar
  27. Cuello, A. C., & Thoenen, H. (1995). The pharmacology of neurotrophic factors. In A. C. Cuello & B. Collier, (Eds.), Pharmacological sciences: perspectives for research and therapy in the late 1990s (pp. 241–254). Basel: Birkhauser.Google Scholar
  28. Czech, C., Forstl, H., Hentschel, F., Monning, U., Besthorn, C., Geiger-Kabisch, C., et al. (1994). Apolipoprotein E-4 gene dose in clinically diagnosed Alzheimer's disease: Prevalence, plasma cholesterol levels and cerebrovascular change. European Archives of Psychiatry and Clinical Neuroscience, 243, 291–292.CrossRefPubMedGoogle Scholar
  29. Davies, P., & Maloney, A. J. (1976). Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet, 2, 1403.CrossRefPubMedGoogle Scholar
  30. De, R. R., Garcia, A. A., Braschi, C., Capsoni, S., Maffei, L., Berardi, N., et al. (2005). Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 102, 3811–3816.CrossRefGoogle Scholar
  31. Debeir, T., Saragovi, H. U., & Cuello, A. C. (1999). A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat. Proceedings of the National Academy of Sciences of the United States of America, 96, 4067–4072.CrossRefPubMedGoogle Scholar
  32. DeKosky, S. T., Harbaugh, R. E., Schmitt, F. A., Bakay, R. A., Chui, H. C., Knopman, D. S., et al. (1992). Cortical biopsy in Alzheimer's disease: Diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group. Annals of Neurology, 32, 625–632.CrossRefPubMedGoogle Scholar
  33. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 383, 710–713.CrossRefPubMedGoogle Scholar
  34. Echeverria, V., Ducatenzeiler, A., Dowd, E., Janne, J., Grant, S. M., Szyf, M., et al. (2004). Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons. Neuroscience, 129, 583–592.CrossRefPubMedGoogle Scholar
  35. Eckman, E. A., & Eckman, C. B. (2005). Abeta-degrading enzymes: Modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochemical Society Symposium, 33, 1101–1105.Google Scholar
  36. Engler, H., Forsberg, A., Almkvist, O., Blomquist, G., Larsson, E., Savitcheva, I., et al. (2006). Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain, 129, 2856–2866.CrossRefPubMedGoogle Scholar
  37. Finch, C. E., & Tanzi, R. E. (1997). Genetics of aging. Science, 278, 407–411.CrossRefPubMedGoogle Scholar
  38. Francis, P. T. (2003). Glutamatergic systems in Alzheimer's disease. International Journal of Geriatric Psychiatry, 18, S15–S21.CrossRefPubMedGoogle Scholar
  39. Friedhoff, P., von, B. M., Mandelkow, E. M., & Mandelkow, E. (2000). Structure of tau protein and assembly into paired helical filaments. Biochimica et Biophysica Acta, 1502, 122–132.PubMedGoogle Scholar
  40. Galasko, D. (2005). Biomarkers for Alzheimer's disease–clinical needs and application. Journal of Alzheimer's Disease, 8, 339–346.PubMedGoogle Scholar
  41. Glenner, G. G., & Wong, C. W. (1984). Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein. Biochemical and Biophysical Research Communications, 122, 1131–1135.CrossRefPubMedGoogle Scholar
  42. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., & 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. Proceedings of the National Academy of Sciences of the United States of America, 85, 4051–4055.CrossRefPubMedGoogle Scholar
  43. Golde, T. E., Eckman, C. B., & Younkin, S. G. (2000). Biochemical detection of Abeta isoforms: Implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochimica et Biophysica Acta, 1502, 172–187.PubMedGoogle Scholar
  44. Gotz, J., Chen, F., van, D. J., & Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science, 293, 1491–1495.CrossRefPubMedGoogle Scholar
  45. Gouras, G. K., Almeida, C. G., & Takahashi, R. H. (2005). Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiology of Aging, 26, 1235–1244.CrossRefPubMedGoogle Scholar
  46. Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., & Wisniewski, H. M. (1986). Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. The Journal of Biological Chemistry, 261, 6084–6089.PubMedGoogle Scholar
  47. Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., & Binder, L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proceedings of the National Academy of Sciences of the United States of America, 83, 4913–4917.CrossRefPubMedGoogle Scholar
  48. Hardy, J. (2004). Toward Alzheimer therapies based on genetic knowledge. Annual Review of Medicine, 55, 15–25.CrossRefPubMedGoogle Scholar
  49. Hardy, J. (2006). Alzheimer's disease: The amyloid cascade hypothesis: An update and reappraisal. Journal of Alzheimer's Disease, 9, 151–153.PubMedGoogle Scholar
  50. Harman, D. (2006). Alzheimer's disease pathogenesis: Role of aging. Annals of the New York Academy of Sciences, 1067, 454–460.CrossRefPubMedGoogle Scholar
  51. Hay, J. W., & Ernst, R. L. (1987). The economic costs of Alzheimer's disease. American Journal of Public Health, 77, 1169–1175.CrossRefPubMedGoogle Scholar
  52. Hu, L., Cote, S. L., & Cuello, A. C. (1997). Differential modulation of the cholinergic phenotype of the nucleus basalis magnocellularis neurons by applying NGF at the cell body or cortical terminal fields. Experimental Neurologyl, 143, 162–171.CrossRefGoogle Scholar
  53. Ikonomovic, M. D., Uryu, K., Abrahamson, E. E., Ciallella, J. R., Trojanowski, J. Q., Lee, V. M., et al. (2004). Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Experimental Neurology, 190, 192–203.CrossRefPubMedGoogle Scholar
  54. Joseph, J. A., Shukitt-Hale, B., & Casadesus, G. (2005). Reversing the deleterious effects of aging on neuronal communication and behavior: Beneficial properties of fruit polyphenolic compounds. The American Journal of Clinical Nutrition, 81, 313S–316S.PubMedGoogle Scholar
  55. Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., et al. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325, 733–736.CrossRefPubMedGoogle Scholar
  56. Katzman, R. (1993). Education and the prevalence of dementia and Alzheimer's disease. Neurology, 43, 13–20.PubMedGoogle Scholar
  57. Kimberly, W. T., Zheng, J. B., Guenette, S. Y., & Selkoe, D. J. (2001). The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. The Journal of Biological Chemistry, 276, 40288–40292.PubMedGoogle Scholar
  58. Kojro, E., & Fahrenholz, F. (2005). The non-amyloidogenic pathway: Structure and function of alpha-secretases. Subcellular Biochemistry, 38, 105–127.CrossRefPubMedGoogle Scholar
  59. Kokmen, E., Beard, C. M., Chandra, V., Offord, K. P., Schoenberg, B. S., & Ballard, D. J. (1991). Clinical risk factors for Alzheimer's disease: A population-based case-control study. Neurology, 41, 1393–1397.PubMedGoogle Scholar
  60. Kosik, K. S., Joachim, C. L., & Selkoe, D. J. (1986). Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 83, 4044–4048.CrossRefPubMedGoogle Scholar
  61. Laakso, M. P., Lehtovirta, M., Partanen, K., Riekkinen, P. J., & Soininen, H. (2000). Hippocampus in Alzheimer's disease: A 3-year follow-up MRI study. Biological Psychiatry, 47, 557–561.CrossRefPubMedGoogle Scholar
  62. Lazarov, O., Robinson, J., Tang, Y. P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M., et al. (2005). Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell, 120, 701–713.CrossRefPubMedGoogle Scholar
  63. Leissring, M. A., Murphy, M. P., Mead, T. R., Akbari, Y., Sugarman, M. C., Jannatipour, M., et al. (2002). A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APP. Proceedings of the National Academy of Sciences of the United States of America, 99, 4697–4702.CrossRefPubMedGoogle Scholar
  64. Lesne, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352–357.CrossRefPubMedGoogle Scholar
  65. Lewis, J., Dickson, D. W., Lin, W. L., Chisholm, L., Corral, A., Jones, G., et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science, 293, 1487–1491.CrossRefPubMedGoogle Scholar
  66. Lye, T. C., & Shores, E. A. (2000). Traumatic brain injury as a risk factor for Alzheimer's disease: A review. Neuropsychology Review, 10, 115–129.CrossRefPubMedGoogle Scholar
  67. Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences of the United States of America, 82, 4245–4249.CrossRefPubMedGoogle Scholar
  68. Mattson, M. P. (2003). Will caloric restriction and folate protect against AD and PD? Neurology, 60, 690–695.CrossRefPubMedGoogle Scholar
  69. Mattson, M. P., Cheng, B., Culwell, A. R., Esch, F. S., Lieberburg, I., & Rydel, R. E. (1993). Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron, 10, 243–254.CrossRefPubMedGoogle Scholar
  70. Mattson, M. P., Guo, Z. H., & Geiger, J. D. (1999). Secreted form of amyloid precursor protein enhances basal glucose and glutamate transport and protects against oxidative impairment of glucose and glutamate transport in synaptosomes by a cyclic GMP-mediated mechanism. Journal of Neurochemistry, 73, 532–537.CrossRefPubMedGoogle Scholar
  71. McGeer, P. L., & McGeer, E. G. (2001). Inflammation, autotoxicity and Alzheimer disease. Neurobiology of Aging, 22, 799–809.CrossRefPubMedGoogle Scholar
  72. McGeer, P. L., Schulzer, M., & McGeer, E. G. (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies. Neurology, 47, 425–432.PubMedGoogle Scholar
  73. McLaurin, J., Kierstead, M. E., Brown, M. E., Hawkes, C. A., Lambermon, M. H. L., Phinney, A. L., et al. (2006). Cyclohexanehexol inhibitors of A beta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nature Medicine, 12, 801–808.CrossRefPubMedGoogle Scholar
  74. Meaney, M. J., & Szyf, M. (2005). Maternal care as a model for experience-dependent chromatin plasticity? Trends in Neurosciences, 28, 456–463.CrossRefPubMedGoogle Scholar
  75. Mena, R., Wischik, C. M., Novak, M., Milstein, C., & 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. Journal of Neuropathology and Experimental Neurology, 50, 474–490.CrossRefPubMedGoogle Scholar
  76. Meziane, H., Dodart, J. C., Mathis, C., Little, S., Clemens, J., Paul, S. M., et al. (1998). Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 12683–12688.CrossRefPubMedGoogle Scholar
  77. Moroney, J. T., Tang, M. X., Berglund, L., Small, S., Merchant, C., Bell, K., et al. (1999). Low-density lipoprotein cholesterol and the risk of dementia with stroke. The Journal of the American Medical Association, 282, 254–260.CrossRefGoogle Scholar
  78. Mosconi, L., Tsui, W. H., De, S. S., Li, J., Rusinek, H., Convit, A., et al. (2005). Reduced hippocampal metabolism in MCI and AD: Automated FDG-PET image analysis. Neurology, 64, 1860–1867.CrossRefPubMedGoogle Scholar
  79. Nitsch, R. M. (1996). From acetylcholine to amyloid: Neurotransmitters and the pathology of Alzheimer's disease. Neurodegeneration, 5, 477–482.CrossRefPubMedGoogle Scholar
  80. Nitsch, R. M., Farber, S. A., Growdon, J. H., & Wurtman, R. J. (1993). Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proceedings of the National Academy of Sciences of the United States of America, 90, 5191–5193.CrossRefPubMedGoogle Scholar
  81. Nitsch, R. M., Slack, B. E., Wurtman, R. J., & Growdon, J. H. (1992). Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science, 258, 304–307.CrossRefPubMedGoogle Scholar
  82. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron, 39, 409–421.CrossRefPubMedGoogle Scholar
  83. Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P., & Gauthier, S. (1993). Apolipoprotein-e Polymorphism and Alzheimers-Disease. Lancet, 342, 697–699.CrossRefPubMedGoogle Scholar
  84. Price, J. C., Klunk, W. E., Lopresti, B. J., Lu, X., Hoge, J. A., Ziolko, S. K., et al. (2005). Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. Journal of Cerebral Blood Flow and Metabolism, 25, 1528–1547.CrossRefPubMedGoogle Scholar
  85. Qiu, C., Winblad, B., & Fratiglioni, L. (2005). The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurology, 4, 487–499.CrossRefPubMedGoogle Scholar
  86. Reichardt, L. F., & Mobley, W. C. (2004). Going the distance, or not, with neurotrophin signals. Cell, 118, 141–143.CrossRefPubMedGoogle Scholar
  87. Roch, J. M., Masliah, E., Roch-Levecq, A. C., Sundsmo, M. P., Otero, D. A., Veinbergs, I., et al. (1994). Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proceedings of the National Academy of Sciences of the United States of America, 91, 7450–7454.CrossRefPubMedGoogle Scholar
  88. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173–177.CrossRefPubMedGoogle Scholar
  89. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996). Secreted amyloid beta-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. Nature Medicine, 2, 864–870.CrossRefPubMedGoogle Scholar
  90. Selkoe, D. J. (2003). Aging, amyloid, and Alzheimer's disease: A perspective in honor of Carl Cotman. Neurochemical Research, 28, 1705–1713.CrossRefPubMedGoogle Scholar
  91. Seshadri, S. (2006). Elevated plasma homocysteine levels: Risk factor or risk marker for the development of dementia and Alzheimer's disease? Journal of Alzheimer's Disease, 9, 393–398.PubMedGoogle Scholar
  92. Sjogren, M., & Blennow, K. (2005). The link between cholesterol and Alzheimer's disease. The World Journal of Biological Psychiatry, 6, 85–97.CrossRefPubMedGoogle Scholar
  93. Skoog, I., & Gustafson, D. (2006). Update on hypertension and Alzheimer's disease. Neurological Research, 28, 605–611.CrossRefPubMedGoogle Scholar
  94. Small, G. W., Kepe, V., Ercoli, L. M., Siddarth, P., Bookheimer, S. Y., Miller, K. J., et al. (2006). PET of brain amyloid and tau in mild cognitive impairment. The New England Journal of Medicine, 355, 2652–2663.CrossRefPubMedGoogle Scholar
  95. Smith, A. D. (2002). Homocysteine, B vitamins, and cognitive deficit in the elderly. The American journal of clinical nutrition, 75, 785–786.PubMedGoogle Scholar
  96. Smith, D. H., Nakamura, M., McIntosh, T. K., Wang, J., Rodriguez, A., Chen, X. H., et al. (1998). Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. The American Journal of Pathology, 153, 1005–1010.PubMedGoogle Scholar
  97. Solomon, B., Koppel, R., Hanan, E., & Katzav, T. (1996). Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proceedings of the National Academy of Sciences of the United States of America, 93, 452–455.CrossRefPubMedGoogle Scholar
  98. Soto, C., Kindy, M. S., Baumann, M., & Frangione, B. (1996). Inhibition of Alzheimer's amyloidosis by peptides that prevent beta-sheet conformation. Biochemical and Biophysical Research Communications, 226, 672–680.CrossRefPubMedGoogle Scholar
  99. Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericakvance, M., et al. (1993). Binding of Human Apolipoprotein-e to Synthetic Amyloid-Beta Peptide - Isoform-Specific Effects and Implications for Late-Onset Alzheimer-Disease. Proceedings of the National Academy of Sciences of the United States of America, 90, 8098–8102.CrossRefPubMedGoogle Scholar
  100. Suzuki, N., Cheung, T. T., Cai, X. D., Odaka, A., Otvos, L., Jr., Eckman, C., et al. (1994). An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science, 264, 1336–1340.CrossRefPubMedGoogle Scholar
  101. Terry, R. D., & Katzman, R. (2001). Life span and synapses: Will there be a primary senile dementia? Neurobiology of Aging, 22, 347–348.CrossRefPubMedGoogle Scholar
  102. Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., et al. (1991). Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30, 572–580.CrossRefPubMedGoogle Scholar
  103. Turner, A. J., Fisk, L., & Nalivaeva, N. N. (2004). Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration. Annals of the New York Academy of Sciences, 1035, 1–20.CrossRefPubMedGoogle Scholar
  104. Tuszynski, M. H., Thal, L., Pay, M., Salmon, D. P., HS, U., Bakay, R., et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11, 551–555.CrossRefPubMedGoogle Scholar
  105. Vassar, R., & Citron, M. (2000). Abeta-generating enzymes: Recent advances in beta- and gamma-secretase research. Neuron, 27, 419–422.CrossRefPubMedGoogle Scholar
  106. Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., et al. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–539.CrossRefPubMedGoogle Scholar
  107. Wang, R., Zhang, Y. W., Sun, P., Liu, R., Zhang, X., Zhang, X., et al. (2006). Transcriptional regulation of PEN-2, a key component of the gamma-secretase complex, by CREB. Molecular and Cellular Biology, 26, 1347–1354.CrossRefPubMedGoogle Scholar
  108. Weaver, C. L., Espinoza, M., Kress, Y., & Davies, P. (2000). Conformational change as one of the earliest alterations of tau in Alzheimer's disease. Neurobiology of Aging, 21, 719–727.CrossRefPubMedGoogle Scholar
  109. Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., et al. (2001). A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212–216.CrossRefPubMedGoogle Scholar
  110. Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & Delon, M. R. (1982). Alzheimer's disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215, 1237–1239.CrossRefPubMedGoogle Scholar
  111. Wolfe, M. S. (2006). The gamma-secretase complex: Membrane-embedded proteolytic ensemble. Biochemistry, 45, 7931–7939.CrossRefPubMedGoogle Scholar
  112. Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., & Selkoe, D. J. (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature, 398, 513–517.CrossRefPubMedGoogle Scholar
  113. Wolozin, B. (2004). Cholesterol, statins and dementia. Current Opinion in Lipidology, 15, 667–672.CrossRefPubMedGoogle Scholar
  114. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., & Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Archives of Neurology, 57, 1439–1443.CrossRefPubMedGoogle Scholar
  115. Wong, C. W., Quaranta, V., & Glenner, G. G. (1985). Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proceedings of the National Academy of Sciences of the United States of America, 82, 8729–8732.CrossRefPubMedGoogle Scholar
  116. Wong, T. P., Debeir, T., Duff, K., & Cuello, A. C. (1999). Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. The Journal of Neuroscience, 19, 2706–2716.PubMedGoogle Scholar
  117. Wood, J. G., Mirra, S. S., Pollock, N. J., & Binder, L. I. (1986). Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proceedings of the National Academy of Sciences of the United States of America, 83, 4040–4043.CrossRefPubMedGoogle Scholar
  118. Zilka, N., Filipcik, P., Koson, P., Fialova, L., Skrabana, R., Zilkova, M., et al. (2006). Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Letters, 580, 3582–3588.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • A. Claudio Cuello
    • 1
  1. 1.Department of Pharmacology and TherapeuticsMcGill UniversityMontrealCanada

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