Two Hits and You’re Out? A Novel Mechanistic Hypothesis of Alzheimer Disease

  • Xiongwei Zhu
  • George Perry
  • Mark A. Smith
Part of the Advances in Behavioral Biology book series (ABBI, volume 57)


Mild Cognitive Impairment Alzheimer Disease Paired Helical Filament Neurobiol Aging Mechanistic Hypothesis 
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.
    Smith MA. Alzheimer disease. Int Rev Neurobiol 1998;42:1–54PubMedGoogle Scholar
  2. 2.
    Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261(5123):921–923PubMedCrossRefGoogle Scholar
  3. 3.
    Roses AD. Apolipoprotein E genotyping in the differential diagnosis, not prediction, of Alzheimer's disease. Ann Neurol 1995;38(1):6–14PubMedCrossRefGoogle Scholar
  4. 4.
    Trojanowski JQ, Schmidt ML, Shin RW, et al. Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol 1993;3(1):45–54PubMedGoogle Scholar
  5. 5.
    Selkoe DJ. Alzheimer's disease: genotypes, phenotypes, and treatments. Science 1997;275(5300):630–631PubMedCrossRefGoogle Scholar
  6. 6.
    Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 1996;274(5284):99–102PubMedCrossRefGoogle Scholar
  7. 7.
    Katzman R. Alzheimer's disease, N Engl J Med1986;314(15):964–973PubMedCrossRefGoogle Scholar
  8. 8.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;11(3):298–300PubMedGoogle Scholar
  9. 9.
    Smith MA, Taneda S, Richey PL, et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 1994;91(12):5710–5714PubMedCrossRefGoogle Scholar
  10. 10.
    Smith MA, Kutty RK, Richey PL, et al. Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am J Pathol 1994;145(1):42–47PubMedGoogle Scholar
  11. 11.
    Smith MA, Rudnicka-Nawrot M, Richey PL, et al. Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J Neurochem 1995;64(6):2660–2666PubMedGoogle Scholar
  12. 12.
    Smith MA, M. Sayre LM, Monnier CM, Perry G. Radical AGEing in Alzheimer's disease. Trends Neurosci 18(4):172–176Google Scholar
  13. 13.
    Smith MA, Sayre LM, Vitek MP, et al. Early AGEing and Alzheimer's. Nature 1995;374(6520):316PubMedCrossRefGoogle Scholar
  14. 14.
    Smith MA, Perry G, Richey PL, et al. Oxidative damage in Alzheimer's. Nature 1996;382(6587):120–121PubMedCrossRefGoogle Scholar
  15. 15.
    Smith MA, Siedlak SL, Richey PL, e al. Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res 1996;717(1-2):99–108PubMedCrossRefGoogle Scholar
  16. 16.
    Smith MA, Richey Harris PL, Sayre LM, et al. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 1997;17(8):2653–2657PubMedGoogle Scholar
  17. 17.
    Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 1997;94(18):9866–9868PubMedCrossRefGoogle Scholar
  18. 18.
    Sayre LM, Zelasko DA, Harris PL, et al. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 1997;68(5):2092–2097PubMedGoogle Scholar
  19. 19.
    Nunomura A, Perry G, Pappolla MA, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci 1999;19(6):1959–1964PubMedGoogle Scholar
  20. 20.
    Nunomura A, Perry G, Pappolla MA, et al. Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 2000;59(11):1011–1017PubMedGoogle Scholar
  21. 21.
    Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001;60(8):759–767PubMedGoogle Scholar
  22. 22.
    Perry G, Castellani RJ, Smith MA, et al. Oxidative damage in the olfactory system in Alzheimer's disease. Acta Neuropathol (Berl) 2003;106(6):552–556CrossRefGoogle Scholar
  23. 23.
    Raina AK, Zhu X, Rottkamp CA, et al. Cyclin' toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res 2000;61(2):128–133PubMedCrossRefGoogle Scholar
  24. 24.
    Bowser R, Smith MA. Cell cycle proteins in Alzheimer's disease: plenty of wheels but no cycle. J Alzheimers Dis 2002;4(3):249–254PubMedGoogle Scholar
  25. 25.
    Sayre LM, Perry G, Harris PL, et al. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. J Neurochem 2000;74(1):270–279PubMedCrossRefGoogle Scholar
  26. 26.
    Oteiza PI. A mechanism for the stimulatory effect of aluminum on iron-induced lipid peroxidation. Arch Biochem Biophys 1994;308(2):374–379PubMedCrossRefGoogle Scholar
  27. 27.
    Good PF, Perl DP, Bierer LM, Schmeidler J. Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study. Ann Neurol 1992;31(3):286–292PubMedCrossRefGoogle Scholar
  28. 28.
    Cras P, Kawai M, Siedlak S, et al. Neuronal and microglial involvement in beta-amyloid protein deposition in Alzheimer's disease. Am J Pathol 1990;137(2):241–246PubMedGoogle Scholar
  29. 29.
    Colton CA, Gilbert DL. Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 1987;223(2):284–288PubMedCrossRefGoogle Scholar
  30. 30.
    Good PF, Werner P, Hsu A, et al. Evidence of neuronal oxidative damage in Alzheimer's disease. Am J Pathol 1996;149(1):21–28PubMedGoogle Scholar
  31. 31.
    Butterfield DA, Hensley K, Harris M, et al. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun 1994;200(2):710–715PubMedCrossRefGoogle Scholar
  32. 32.
    Butterfield DA, Bush AI. Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Neurobiol Aging 2004;25(5):563–568PubMedCrossRefGoogle Scholar
  33. 33.
    Hensley K, Carney JM, Mattson MP, et al. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A 1994;91(8):3270–3274PubMedCrossRefGoogle Scholar
  34. 34.
    Sayre LM, Zagorski MG, Surewicz WK, et al. Mechanisms of neurotoxicity associated with amyloid beta deposition and the role of free radicals in the pathogenesis of Alzheimer's disease: a critical appraisal. Chem Res Toxicol 1997;10(5):518-526PubMedCrossRefGoogle Scholar
  35. 35.
    Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991;40(4):405-412PubMedCrossRefGoogle Scholar
  36. 36.
    Yan SD, Yan SF, Chen X, et al. Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1995;1(7):693–699PubMedCrossRefGoogle Scholar
  37. 37.
    Yan SD, Chen X, Schmidt AM, et al. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 1994;91(16):7787–7791PubMedCrossRefGoogle Scholar
  38. 38.
    Munch G, Kuhla B, Luth HJ, et al. Anti-AGEing defences against Alzheimer's disease. Biochem Soc Trans 2003;31(Pt 6):1397–1399PubMedGoogle Scholar
  39. 39.
    El Khoury J, Hickman SE, Thomas CA, et al. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 1996;382(6593):716–719PubMedCrossRefGoogle Scholar
  40. 40.
    Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382(6593):685–691Google Scholar
  41. 41.
    Davis RE, Miller S, Herrnstadt C, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc Natl Acad Sci USA 1997;94(9):4526–4531PubMedCrossRefGoogle Scholar
  42. 42.
    Hirai K, Aliev G, Nunomura A, et al. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 2001;21(9):3017–3023PubMedGoogle Scholar
  43. 43.
    Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A 2004;101(29):10726–10731PubMedCrossRefGoogle Scholar
  44. 44.
    Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease. Science 2004;304(5669):448-452PubMedCrossRefGoogle Scholar
  45. 45.
    Manczak M, Park BS, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromol Med 2004;5(2):147–162CrossRefGoogle Scholar
  46. 46.
    Trimmer PA, Keeney PM, Borland MK, et al. Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture. Neurobiol Dis 2004;15(1):29–39PubMedCrossRefGoogle Scholar
  47. 47.
    Williamson KS, Gabbita SP, Mou S, et al. The nitration product 5-nitro-gamma-tocopherol is increased in the Alzheimer brain. Nitric Oxide 2002;6(2):221–227PubMedCrossRefGoogle Scholar
  48. 48.
    Castegna A, Thongboonkerd V, Klein JB, et al. Proteomic identification of nitrated proteins in Alzheimer's disease brain. J Neurochem 2003;85(6):1394–1401PubMedCrossRefGoogle Scholar
  49. 49.
    Palmer AM, Burns MA, Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer's disease. Brain Res 1994;645(1-2):338–342PubMedCrossRefGoogle Scholar
  50. 50.
    Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med 2001;7(12):548–554PubMedCrossRefGoogle Scholar
  51. 51.
    Tamaoka A, Miyatake F, Matsuno S, et al. Apolipoprotein E allele-dependent antioxidant activity in brains with Alzheimer's disease. Neurology 2000;54(12):2319–2321PubMedGoogle Scholar
  52. 52.
    Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease. Neurology 1995;45(8):1594–1601PubMedGoogle Scholar
  53. 53.
    Markesbery WR, Lovell MA, Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Neurobiol Aging 1998;19(1):33–36PubMedCrossRefGoogle Scholar
  54. 54.
    Guan Z, Wang Y, Cairns NJ, et al. Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J Neuropathol Exp Neurol 1999;58(7):740–747PubMedGoogle Scholar
  55. 55.
    Wataya T, Nunomura A, Smith MA, et al. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem 2002;277(7):4644–4648PubMedCrossRefGoogle Scholar
  56. 56.
    Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88(23):10540–10543PubMedCrossRefGoogle Scholar
  57. 57.
    Ledesma MD, Bonay P, Colaco C, Avila J. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 1994;269(34):21614–21619PubMedGoogle Scholar
  58. 58.
    Vitek MP, Bhattacharya K, Glendening JM, et al. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA 1994;91(11):4766–4770PubMedCrossRefGoogle Scholar
  59. 59.
    Montine TJ, Amarnath V, Martin ME, et al. E-4-hydroxy-2-nonenal is cytotoxic and cross-links cytoskeletal proteins in P19 neuroglial cultures. Am J Pathol 1996;148(1):89–93PubMedGoogle Scholar
  60. 60.
    Takeda A, Smith MA, Avila J, et al. In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem 2000;75(3):1234–1241PubMedCrossRefGoogle Scholar
  61. 61.
    Cras P, Smith MA, Richey PL, et al. Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathol (Berl) 1995;89(4):291–295CrossRefGoogle Scholar
  62. 62.
    Friguet B, Stadtman ER, Szweda LI, Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal: formation of cross-linked protein that inhibits the multi-catalytic protease. J Biol Chem 1994;269(34):21639–21643PubMedGoogle Scholar
  63. 63.
    Perry G, Mulvihill P, Manetto V, et al. Immunocytochemical properties of Alzheimer straight filaments. J Neurosci 1987;7(11):3736–3738PubMedGoogle Scholar
  64. 64.
    Smith MA, Perry G. Alzheimer disease: an imbalance of proteolytic regulation? Med Hypotheses 1994;42(4):277–279PubMedCrossRefGoogle Scholar
  65. 65.
    Galloway PG, Grundke-Iqbal I, Iqbal K, Perry G. Lewy bodies contain epitopes both shared and distinct from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol 1988;47(6):654–663PubMedGoogle Scholar
  66. 66.
    Manetto V, Abdul-Karim FW, Perry G, et al. Selective presence of ubiquitin in intracellular inclusions. Am J Pathol 1989;134(3):505–513PubMedGoogle Scholar
  67. 67.
    Castellani R, Smith MA, Richey PL, et al. Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res 1995;696(1-2):268–271PubMedCrossRefGoogle Scholar
  68. 68.
    Castellani R, Smith MA, Richey PL, Perry G. Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res 1996;737(1-2):195–200PubMedCrossRefGoogle Scholar
  69. 69.
    Castellani RJ, Perry G, Harris PL, et al. Advanced glycation modification of Rosenthal fibers in patients with Alexander disease. Neurosci Lett 1997;231(2):79–82PubMedCrossRefGoogle Scholar
  70. 70.
    Pappolla MA, Omar RA, Kim KS, Robakis NK. Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease. Am J Pathol 1992;140(3):621–628PubMedGoogle Scholar
  71. 71.
    Aksenov MY, Tucker HM, Nair P, et al. The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease. J Mol Neurosci 1998;11(2):151–164PubMedCrossRefGoogle Scholar
  72. 72.
    Lee SC, Zhao ML, Hirano A, Dickson DW, Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangles, and senile plaques. J Neuropathol Exp Neurol 1999;58(11):1163–1169PubMedGoogle Scholar
  73. 73.
    Perry G, Smith MA. Is oxidative damage central to the pathogenesis of Alzheimer disease? Acta Neurol Belg 1998;98(2):175–179PubMedGoogle Scholar
  74. 74.
    Nunomura A, Chiba S, Lippa CF, et al. Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol Dis 2004;17(1):108–113PubMedCrossRefGoogle Scholar
  75. 75.
    Pratico D, Uryu K, Leight S, et al. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 2001;21(12):4183–4187PubMedGoogle Scholar
  76. 76.
    Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease: The Alzheimer's Disease Cooperative Study. N Engl J Med 1997;336(17):1216–1222PubMedCrossRefGoogle Scholar
  77. 77.
    Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997;48(3):626–632PubMedGoogle Scholar
  78. 78.
    Pratico D, Lee MY V, Trojanowski JQ, et al. Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo. FASEB J 1998;12(15):1777–1783PubMedGoogle Scholar
  79. 79.
    Pratico D, Clark CM, Lee VM, et al. Increased 8,12-iso-iPF2alpha-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48(5):809–812PubMedCrossRefGoogle Scholar
  80. 80.
    Pratico D, Clark CM, Liun F, et al. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 2002;59(6):972–976PubMedCrossRefGoogle Scholar
  81. 81.
    Odetti P, Angelini G, Dapino D, et al. Early glycoxidation damage in brains from Down's syndrome. Biochem Biophys Res Commun 1998;243(3):849–851PubMedCrossRefGoogle Scholar
  82. 82.
    Smith MA, Hirai K, Hsiao K, et al. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 1998;70(5):2212–2215PubMedCrossRefGoogle Scholar
  83. 83.
    Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 1995;11(2):211–219PubMedGoogle Scholar
  84. 84.
    Sherr CJ. G1 phase progression: cycling on cue. Cell 1994;79(4):551–555PubMedCrossRefGoogle Scholar
  85. 85.
    Meikrantz W, Schlegel R. Apoptosis and the cell cycle. J Cell Biochem 1995;58(2):160–174PubMedCrossRefGoogle Scholar
  86. 86.
    Smith TW, Lippa CF. Ki-67 immunoreactivity in Alzheimer's disease and other neurodegenerative disorders. J Neuropathol Exp Neurol 1995;54(3):297–303PubMedCrossRefGoogle Scholar
  87. 87.
    McShea A, Harris PL, Webster KE, et al. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol 1997;150(6):1933–1939PubMedGoogle Scholar
  88. 88.
    Nagy Z, Esiri MM, Smith AD. Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol (Berl) 1997;93(3):294–300CrossRefGoogle Scholar
  89. 89.
    Nagy Z, Esiri MM, Cato AM, Smith AD. Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol (Berl) 1997;94(1):6–15CrossRefGoogle Scholar
  90. 90.
    Harris PL, Zhu X, Pamies C, et al. Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes. Neurobiol Aging 2000;21(6):837–841PubMedCrossRefGoogle Scholar
  91. 91.
    Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 2001;21(8):2661–2668PubMedGoogle Scholar
  92. 92.
    Ogawa O, Lee HG, Zhu X, et al. Increased p27, an essential component of cell cycle control, in Alzheimer's disease. Aging Cell 2003;2(2):105–110PubMedCrossRefGoogle Scholar
  93. 93.
    Ogawa O, Zhu X, H. G. Lee HG, et al. Ectopic localization of phosphorylated histone H3 in Alzheimer's disease: a mitotic catastrophe? Acta Neuropathol (Berl) 2003;105(5):524–528Google Scholar
  94. 94.
    Zhu X, McShea A, Harris PL, et al. Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease. J Neurosci Res 2004;75(5):698–703PubMedCrossRefGoogle Scholar
  95. 95.
    Zhu X, Raina AK, Smith MA. Cell cycle events in neurons: proliferation or death? Am J Pathol 1999;155(2):327–329PubMedGoogle Scholar
  96. 96.
    Vincent I, Jicha G, Rosado M, Dickson DW. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci 1997;17(10):3588–3598PubMedGoogle Scholar
  97. 97.
    Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci 1998;18(8):2801–2807PubMedGoogle Scholar
  98. 98.
    Zhu X, Rottkamp CA, Raina AK, et al. Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiol Aging 2000;21(6):807–813PubMedCrossRefGoogle Scholar
  99. 99.
    Vincent I, Zheng JH, Dickson DW, et al. Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease. Neurobiol Aging 1998;19(4):287–296PubMedCrossRefGoogle Scholar
  100. 100.
    Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci 2003;23(7):2557–2563PubMedGoogle Scholar
  101. 101.
    Zhu X, Raina AK, Perry G, Smith MA. Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 2004;3(4):219–226PubMedCrossRefGoogle Scholar
  102. 102.
    Perry G, Nunomura A, Smith MA. A suicide note from Alzheimer disease neurons? Nat Med 1998;4(8):897–898PubMedCrossRefGoogle Scholar
  103. 103.
    Perry G, Zhu X, Smith MA. Do neurons have a choice in death? Am J Pathol 2001;158(1):1–2PubMedGoogle Scholar
  104. 104.
    Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci U S A 1989;86(1):99–103PubMedCrossRefGoogle Scholar
  105. 105.
    Rushmore TH, King RG, Paulson KE, Pickett DB. Regulation of glutathione S-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds. Proc Natl Acad Sci U S A 1990;87(10):3826–3830PubMedCrossRefGoogle Scholar
  106. 106.
    Davies JM, Lowry CV, Davies KJ. Transient adaptation to oxidative stress in yeast. Arch Biochem Biophys 1995;317(1):1–6PubMedCrossRefGoogle Scholar
  107. 107.
    Wiese AG, Pacifici RE, Davies KJ. Transient adaptation of oxidative stress in mammalian cells. Arch Biochem Biophys 1995;318(1):231–240PubMedCrossRefGoogle Scholar
  108. 108.
    LeBel CP, Bondy SC. Oxidative damage and cerebral aging. Prog Neurobiol 1992;38(6):601–609PubMedCrossRefGoogle Scholar
  109. 109.
    Chao M, Zhu X, Raina AK, et al. Sources contributing to the initiation and propagation of oxidative stress in Alzheimer disease. Proc Indian Natl Sci Acad Part B 2003;69:251–260Google Scholar
  110. 110.
    Mattson MP, Chan SL, Duan W. Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 2002;82(3):637–672PubMedGoogle Scholar
  111. 111.
    Allen SJ, MacGowan SH, Treanor JJ, et al. Normal beta-NGF content in Alzheimer's disease cerebral cortex and hippocampus. Neurosci Lett 1991;131(1):135–139PubMedCrossRefGoogle Scholar
  112. 112.
    Crutcher KA, Scott SA, Liang S, et al. Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer's disease. J Neurosci 1993;13(6):2540–2550PubMedGoogle Scholar
  113. 113.
    Connor B, Young D, Lawlor P, et al. Trk receptor alterations in Alzheimer's disease. Brain Res Mol Brain Res 1996;42(1):1–17PubMedCrossRefGoogle Scholar
  114. 114.
    Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 1997;20(4):154–159PubMedCrossRefGoogle Scholar
  115. 115.
    Chen Y, McPhie DL, Hirschberg L, Neve RL. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem 2000;275(12):8929–8935PubMedCrossRefGoogle Scholar
  116. 116.
    Neve RL, McPhie DL, Chen Y. Alzheimer's disease: a dysfunction of the amyloid precursor protein(1). Brain Res 2000;886(1-2):54–66PubMedCrossRefGoogle Scholar
  117. 117.
    Bruni P, Minopoli G, Brancaccio Y, et al. Fe65, a ligand of the Alzheimer's beta-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression. J Biol Chem 2002;277(38):35481–35488PubMedCrossRefGoogle Scholar
  118. 118.
    Schubert D, Cole G, Saitoh Y, Oltersdorf T. Amyloid beta protein precursor is a mitogen. Biochem Biophys Res Commun 1989;162(1):83–88PubMedCrossRefGoogle Scholar
  119. 119.
    Milward EA, Papadopoulos R, Fuller SJ, et al. The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 1992;9(1):129–137PubMedCrossRefGoogle Scholar
  120. 120.
    Copani A, Condorelli F, Caruso A, et al. Mitotic signaling by beta-amyloid causes neuronal death. FASEB J 1999;13(15):2225–2234PubMedGoogle Scholar
  121. 121.
    Hoffmann J, Twiesselmann C, Kummer MP, et al. A possible role for the Alzheimer amyloid precursor protein in the regulation of epidermal basal cell proliferation. Eur J Cell Biol 2000;79(12):905–914PubMedCrossRefGoogle Scholar
  122. 122.
    Schmitz A, Tikkanen R, Kirfel G, Herzog V. The biological role of the Alzheimer amyloid precursor protein in epithelial cells. Histochem Cell Biol 2002;117(2):171–180PubMedCrossRefGoogle Scholar
  123. 123.
    Eckert A, Steiner B, Marques C, et al. Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. J Neurosci Res 2001;64(2):183–192PubMedCrossRefGoogle Scholar
  124. 124.
    Marques CA, Keil U, Bonert A, et al. Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J Biol Chem 2003;278(30):28294–28302PubMedCrossRefGoogle Scholar
  125. 125.
    Leutz S, Steiner B, Marques CA, et al. Reduction of trophic support enhances apoptosis in PC12 cells expressing Alzheimer's APP mutation and sensitizes cells to staurosporine-induced cell death. J Mol Neurosci 2002;18(3):189–201PubMedCrossRefGoogle Scholar
  126. 126.
    Xu X, Yang D, Wyss-Coray T, et al. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A 1999;96(13):7547–7552PubMedCrossRefGoogle Scholar
  127. 127.
    Koistinaho M, Kettunen MI, Goldsteins G, et al. 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 2002;99(3):1610–1615PubMedCrossRefGoogle Scholar
  128. 128.
    Nakagawa Y, Nakamura M, McIntosh TK, et al. Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Aβ deposition during aging. J Comp Neurol 1999;411(3):390–398PubMedCrossRefGoogle Scholar
  129. 129.
    Janicki SM, Monteiro MJ. Presenilin overexpression arrests cells in the G1 phase of the cell cycle: arrest potentiated by the Alzheimer's disease PS2(N141I) mutant. Am J Pathol 1999;155(1):135–144PubMedGoogle Scholar
  130. 130.
    Janicki SM, Stabler SM, Monteiro MJ. Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging 2000;21(6):829–836PubMedCrossRefGoogle Scholar
  131. 131.
    Prat MI, Adamo AM, Gonzalez SA, et al. Presenilin 1 overexpressions in Chinese hamster ovary (CHO) cells decreases the phosphorylation of retinoblastoma protein: relevance for neurodegeneration. Neurosci Lett 2002;326(1):9–12PubMedCrossRefGoogle Scholar
  132. 132.
    Soriani M, Pietraforte D, Minetti M. Antioxidant potential of anaerobic human plasma: role of serum albumin and thiols as scavengers of carbon radicals. Arch Biochem Biophys 1994;312(1):180–188PubMedCrossRefGoogle Scholar
  133. 133.
    Yuasa S, Nakajima M, Aizawa H, et al. Impaired cell cycle control of neuronal precursor cells in the neocortical primordium of presenilin-1-deficient mice. J Neurosci Res 2002;70(3):501–513.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Xiongwei Zhu
    • 1
  • George Perry
  • Mark A. Smith
  1. 1.Department of PathologyCase Western Reserve UniversityClevelandUSA

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