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Physiologic and Neurotoxic Properties of Aβ Peptides

  • Gillian C. Gregory
  • Claire E. Shepherd
  • Glenda M. Halliday

Abstract

Alzheimer’s disease (AD) is characterized by a gradual decline of numerous cognitive processes, culminating in dementia and neurodegeneration. It is the most common form of dementia and a significant cause of death in the elderly. Definitive diagnosis of AD requires the presence of the extracellular accumulation of Aβ peptides in senile plaques in the cortex of the brain (Fig. 11.1) [1]. β-Amyloid (Aβ) peptides are ∼4-kDa polypeptides with the main alloforms consisting of 40 and 42 amino acids. Analysis of the insoluble protein fraction has identified the longer Aβ42 alloform as the predominant peptide species in the neuropathologic accumulations (see [2]), although Aβ peptides of variable length accumulate within plaques [3]–[8]. The association between the abnormal accumulation of Aβ peptides in the brain and dementia is strong evidence that Aβ peptides are vital for normal brain functioning.

Keywords

Amyloid Precursor Protein Amyloid Beta Neurobiol Aging Amyloid Beta Protein Neurotoxic Property 
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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References

  1. 1.
    Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–90.PubMedGoogle Scholar
  2. 2.
    Gregory GC, Halliday GM. What is the dominant Abeta species in human brain tissue? A review. Neurotox Res 2005;7:29–41.PubMedGoogle Scholar
  3. 3.
    Funato H, Yoshimura M, Kusui K, et al. Quantitation of amyloid beta-protein (A beta) in the cortex during aging and in Alzheimer’s disease. Am J Pathol 1998;152:1633–40.PubMedGoogle Scholar
  4. 4.
    Fukumoto H, Asami-Odaka A, Suzuki N, et al. Association of A beta 40-positive senile plaques with microglial cells in the brains of patients with Alzheimer’s disease and in non-demented aged individuals. Neurodegeneration 1996;5:13–7.PubMedGoogle Scholar
  5. 5.
    Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994;13:45–53.PubMedGoogle Scholar
  6. 6.
    Roher AE, Lowenson JD, Clarke S, et al. beta-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer’s disease. Proc Natl Acad Sci U S A 1993;90:10836–40.Google Scholar
  7. 7.
    Mann DM, Iwatsubo T, Fukumoto H, et al. Microglial cells and amyloid beta protein [A beta] deposition; association with A beta 40-containing plaques. Acta Neuropathol (Berlin) 1995;90:472–7.PubMedGoogle Scholar
  8. 8.
    Mann DM, Iwatsubo T, Pickering-Brown SM, et al. Preferential deposition of amyloid beta protein (Abeta) in the form Abeta40 in Alzheimer’s disease is associated with a gene dosage effect of the apolipoprotein E E4 allele. Neurosci Lett 1997;221:81–4.PubMedGoogle Scholar
  9. 9.
    Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704–6.PubMedGoogle Scholar
  10. 10.
    Van Broeckhoven C, Haan J, Bakker E, et al. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 1990;248:1120–2.PubMedGoogle Scholar
  11. 11.
    Borchelt DR, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997;19:939–45.PubMedGoogle Scholar
  12. 12.
    Games D, Adams D, Alessandrini R, et al. Alzheimer’s-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995;373:523–7.PubMedGoogle Scholar
  13. 13.
    Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274: 99–102.PubMedGoogle Scholar
  14. 14.
    Suzuki N, Cheung TT, Cai XD, et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994;264:1336–40.PubMedGoogle Scholar
  15. 15.
    Tamaoka A, Odaka A, Ishibashi Y, et al. APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1–42/43 and a beta 1–40) in familial Alzheimer’s disease brain. J Biol Chem 1994;269:32721–4.PubMedGoogle Scholar
  16. 16.
    Scheuner D, Eckman C, Jensen M, et al. 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. Nat Med 1996;2:864–70.PubMedGoogle Scholar
  17. 17.
    Haass C, Schlossmacher MG, Hung AY, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322–5.PubMedGoogle Scholar
  18. 18.
    Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–66.PubMedGoogle Scholar
  19. 19.
    Tanaka S, Shiojiri S, Takahashi Y, et al. Tissue-specific expression of three types of beta-protein precursor mRNA: enhancement of protease inhibitor-harboring types in Alzheimer’s disease brain. Biochem Biophys Res Commun 1989;165: 1406–14.PubMedGoogle Scholar
  20. 20.
    Kamal A, Almenar-Queralt A, LeBlanc JF, et al. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 2001;414:643–8.PubMedGoogle Scholar
  21. 21.
    Turner PR, O’Connor K, Tate WP, et al. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 2003;70:1–32.PubMedGoogle Scholar
  22. 22.
    Haass C, Hung AY, Schlossmacher MG, et al. beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 1993;268:3021–4.PubMedGoogle Scholar
  23. 23.
    Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta-and gamma-secretases. FEBS Lett 2000;483:6–10.PubMedGoogle Scholar
  24. 24.
    Brown MS, Ye J, Rawson RB, et al. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000;100:391–8.PubMedGoogle Scholar
  25. 25.
    Ulery PG, Beers J, Mikhailenko I, et al. Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer’s disease. J Biol Chem 2000;275:7410–5.PubMedGoogle Scholar
  26. 26.
    Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735–41.PubMedGoogle Scholar
  27. 27.
    Cook DG, Forman MS, Sung JC, et al. Alzheimer’s A beta(1–42) is generated in the endoplasmic reticulum/ intermediate compartment of NT2N cells. Nat Med 1997;3:1021–3.PubMedGoogle Scholar
  28. 28.
    Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000;407:48–54.PubMedGoogle Scholar
  29. 29.
    Esler WP, Kimberly WT, Ostaszewski BL, et al. Activity-dependent isolation of the presenilingamma-secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci U S A 2002;99:2720–5.PubMedGoogle Scholar
  30. 30.
    Goutte C, Tsunozaki M, Hale VA, et al. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002;99:775–9.PubMedGoogle Scholar
  31. 31.
    Francis R, McGrath G, Zhang J, et al. aph-1 and pen-2 are required for Notch pathway signaling, gammasecretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002;3:85–97.PubMedGoogle Scholar
  32. 32.
    Gu Y, Sanjo N, Chen F, et al. The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities. J Biol Chem 2004;279:31329–36.PubMedGoogle Scholar
  33. 33.
    Ida N, Hartmann T, Pantel J, et al. Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 1996;271:22908–14.PubMedGoogle Scholar
  34. 34.
    Tamaoka A, Sawamura N, Fukushima T, et al. Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci 1997;148:41–5.PubMedGoogle Scholar
  35. 35.
    Mehta PD, Pirttila T, Mehta SP, et al. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer’s disease. Arch Neurol 2000;57:100–5.PubMedGoogle Scholar
  36. 36.
    Shoji M. Cerebrospinal fluid Abeta40 and Abeta42: natural course and clinical usefulness. Front Biosci 2002;7:d997–1006.Google Scholar
  37. 37.
    Nakamura T, Shoji M, Harigaya Y, et al. Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer’s disease. Ann Neurol 1994;36:903–11.PubMedGoogle Scholar
  38. 38.
    Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995;38:643–8.PubMedGoogle Scholar
  39. 39.
    Shoji M, Matsubara E, Kanai M, et al. Combination assay of CSF tau, A beta 1–40 and A beta 1–42(43) as a biochemical marker of Alzheimer’s disease. J Neurol Sci 1998;158:134–40.PubMedGoogle Scholar
  40. 40.
    Samuels SC, Silverman JM, Marin DB, et al. CSF beta-amyloid, cognition, and APOE genotype in Alzheimer’s disease. Neurology 1999;52:547–51.PubMedGoogle Scholar
  41. 41.
    Andreasen N, Hesse C, Davidsson P, et al. Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer’s disease: differences between early-and late-onset Alzheimer’s disease and stability during the course of disease. Arch Neurol 1999;56:673–80.PubMedGoogle Scholar
  42. 42.
    Tapiola T, Pirttila T, Mehta PD, et al. Relationship between apoE genotype and CSF beta-amyloid (1–42) and tau in patients with probable and definite Alzheimer’s disease. Neurobiol Aging 2000;21:735–40.PubMedGoogle Scholar
  43. 43.
    Tapiola T, Pirttila T, Mikkonen M, et al. Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer’s disease. Neurosci Lett 2000;280:119–22.PubMedGoogle Scholar
  44. 44.
    Kanai M, Matsubara E, Isoe K, et al. Longitudinal study of cerebrospinal fluid levels of tau, A beta1–40, and A beta1–42(43) in Alzheimer’s disease: a study in Japan. Ann Neurol 1998;44:17–26.PubMedGoogle Scholar
  45. 45.
    Mayeux R, Tang MX, Jacobs DM, et al. Plasma amyloid beta-peptide 1–42 and incipient Alzheimer’s disease. Ann Neurol 1999;46:412–6.PubMedGoogle Scholar
  46. 46.
    Hoglund K, Wiklund O, Vanderstichele H, et al. Plasma levels of beta-amyloid(1–40), beta-amyloid( 1–42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol 2004;61:333–7.PubMedGoogle Scholar
  47. 47.
    Hampel H, Mitchell A, Blennow K, et al. Core biological marker candidates of Alzheimer’s disease-perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm 2004;111:247–72.PubMedGoogle Scholar
  48. 48.
    Tamaoka A, Fukushima T, Sawamura N, et al. Amyloid beta protein in plasma from patients with sporadic Alzheimer’s disease. J Neurol Sci 1996;141:65–8.PubMedGoogle Scholar
  49. 49.
    Kuo YM, Emmerling MR, Lampert HC, et al. High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun 1999;257:787–91.PubMedGoogle Scholar
  50. 50.
    Andreasen N, Minthon L, Vanmechelen E, et al. Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett 1999;273:5–8.PubMedGoogle Scholar
  51. 51.
    Shoji M, Kanai M, Matsubara E, et al. Taps to Alzheimer’s patients: a continuous Japanese study of cerebrospinal fluid biomarkers. Ann Neurol 2000;48:402.Google Scholar
  52. 52.
    Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreased beta-amyloid1–42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology 2000;54:1099–102.PubMedGoogle Scholar
  53. 53.
    Kanemaru K, Kameda N, Yamanouchi H. Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies. Neurology 2000;54:1875–6.PubMedGoogle Scholar
  54. 54.
    Li QX, Fuller SJ, Beyreuther K, et al. The amyloid precursor protein of Alzheimer’s disease in human brain and blood. J Leukoc Biol 1999;66:567–74.PubMedGoogle Scholar
  55. 55.
    Wild-Bode C, Yamazaki T, Capell A, et al. Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 1997;272:16085–8.PubMedGoogle Scholar
  56. 56.
    Hartmann T, Bieger SC, Bruhl B, et al. Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 1997;3:1016–20.PubMedGoogle Scholar
  57. 57.
    Hershkowitz M, Adunsky A. Binding of plateletactivating factor to platelets of Alzheimer’s disease and multiinfarct dementia patients. Neurobiol Aging 1996;17:865–8.PubMedGoogle Scholar
  58. 58.
    Borroni B, Colciaghi F, Caltagirone C, et al. Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer’s type: a 2-year follow-up study. Arch Neurol 2003;60:1740–4.PubMedGoogle Scholar
  59. 59.
    Zlokovic BV. Cerebrovascular transport of Alzheimer’s amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the bloodbrain barrier. Life Sci 1996;59:1483–97.PubMedGoogle Scholar
  60. 60.
    Mackic J, Ghiso J, Frangione B, et al. Differential cerebrovascular sequestration and enhanced bloodbrain barrier permeability to circulating Alzheimer’s amyloid-β peptide in aged Rhesus vs. aged Squirrel monkey. Vascular Pharmacol 2002;18:303–13.Google Scholar
  61. 61.
    Rhodin JA, Thomas TN, Clark L, et al. In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens. J Alzheimers Dis 2003;5:275–86.PubMedGoogle Scholar
  62. 62.
    Kawarabayashi T, Younkin LH, Saido TC, et al. Agedependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 2001;21:372–81.PubMedGoogle Scholar
  63. 63.
    DeMattos RB, Bales KR, Cummins DJ, et al. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002;295:2264–7.PubMedGoogle Scholar
  64. 64.
    Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–5.PubMedGoogle Scholar
  65. 65.
    Naslund J, Schierhorn A, Hellman U, et al. Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer’s disease and normal aging. Proc Natl Acad Sci U S A 1994;91:8378–82.PubMedGoogle Scholar
  66. 66.
    Tamaoka A, Kondo T, Odaka A, et al. Biochemical evidence for the long-tail form (A beta 1–42/43) of amyloid beta protein as a seed molecule in cerebral deposits of Alzheimer’s disease. Biochem Biophys Res Commun 1994;205:834–42.PubMedGoogle Scholar
  67. 67.
    Gravina SA, Ho L, Eckman CB, et al. Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995;270:7013–6.PubMedGoogle Scholar
  68. 68.
    Kuo YM, Emmerling MR, Vigo-Pelfrey C, et al. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer’s disease brains. J Biol Chem 1996;271:4077–81.PubMedGoogle Scholar
  69. 69.
    Shinkai Y, Yoshimura M, Morishima-Kawashima M, et al. Amyloid beta-protein deposition in the leptomeninges and cerebral cortex. Ann Neurol 1997;42:899–908.PubMedGoogle Scholar
  70. 70.
    Tamaoka A, Fraser PE, Ishii K, et al. Amyloid-betaprotein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer’s disease. Brain Res Mol Brain Res 1998;56:178–85.PubMedGoogle Scholar
  71. 71.
    Kuo YM, Emmerling MR, Bisgaier CL, et al. Elevated low-density lipoprotein in Alzheimer’s disease correlates with brain abeta 1–42 levels. Biochem Biophys Res Commun 1998;252:711–5.PubMedGoogle Scholar
  72. 72.
    Lue LF, Kuo YM, Roher AE, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 1999;155:853–62.PubMedGoogle Scholar
  73. 73.
    Beffert U, Cohn JS, Petit-Turcotte C, et al. Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer’s disease subjects are disease-related and apolipoprotein E genotype dependent. Brain Res 1999;843:87–94.PubMedGoogle Scholar
  74. 74.
    Wang J, Dickson DW, Trojanowski JQ, et al. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp Neurol 1999;158:328–37.PubMedGoogle Scholar
  75. 75.
    Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571–7.PubMedGoogle Scholar
  76. 76.
    Morishima-Kawashima M, Oshima N, Ogata H, et al. Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain. Am J Pathol 2000;157:2093–9.PubMedGoogle Scholar
  77. 77.
    Miklossy J, Taddei K, Suva D, et al. Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease. Neurobiol Aging 2003;24:655–62.PubMedGoogle Scholar
  78. 78.
    Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004;62:925–31.PubMedGoogle Scholar
  79. 79.
    Li R, Lindholm K, Yang LB, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci U S A 2004;101:3632–7.PubMedGoogle Scholar
  80. 80.
    Turner RS, Suzuki N, Chyung AS, et al. Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 1996;271:8966–70.PubMedGoogle Scholar
  81. 81.
    Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 2001;24: 219–24.PubMedGoogle Scholar
  82. 82.
    Walsh DM, Lomakin A, Benedek GB, et al. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem 1997;272:22364–72.PubMedGoogle Scholar
  83. 83.
    Hartley DM, Walsh DM, Ye CP, et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 1999;19:8876–84.PubMedGoogle Scholar
  84. 84.
    Nilsberth C, Westlind-Danielsson A, Eckman CB, et al. The’ Arctic’ APP mutation [E693G] causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 2001;4:887–93.PubMedGoogle Scholar
  85. 85.
    Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002;416:535–9.PubMedGoogle Scholar
  86. 86.
    Bitan G, Vollers SS, Teplow DB. Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization. J Biol Chem 2003;278:34882–9.PubMedGoogle Scholar
  87. 87.
    Bitan G, Kirkitadze MD, Lomakin A, et al. Amyloid beta-protein [Abeta] assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A 2003;100:330–5.PubMedGoogle Scholar
  88. 88.
    Xu Y, Shen J, Luo X, et al. Conformational transition of amyloid beta-peptide. Proc Natl Acad Sci U S A 2005;102:5403–7.PubMedGoogle Scholar
  89. 89.
    Coles M, Bicknell W, Watson AA, et al. Solution structure of amyloid beta-peptide(1–40) in a watermicelle environment. Is the membrane-spanning domain where we think it is? Biochemistry 1998;37:11064–77.PubMedGoogle Scholar
  90. 90.
    Soto C, Castano EM, Frangione B, et al. The alphahelical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. J Biol Chem 1995;270:3063–7.PubMedGoogle Scholar
  91. 91.
    Mager PP. Molecular simulation of the primary and secondary structures of the Abeta(1–42)-peptide of Alzheimer’s disease. Med Res Rev 1998;18:403–30.PubMedGoogle Scholar
  92. 92.
    Kirkitadze MD, Condron MM, Teplow DB. Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol 2001;312:1103–19.PubMedGoogle Scholar
  93. 93.
    Serpell LC. Alzheimer’s amyloid fibrils: structure and assembly. Biochim Biophys Acta 2000;1502:16–30.PubMedGoogle Scholar
  94. 94.
    Good TA, Murphy RM. Aggregation state-dependent binding of beta-amyloid peptide to protein and lipid components of rat cortical homogenates. Biochem Biophys Res Commun 1995;207:209–15.PubMedGoogle Scholar
  95. 95.
    Temussi PA, Masino L, Pastore A. From Alzheimer to Huntington: why is a structural understanding so difficult? Embo J 2003;22:355–61.PubMedGoogle Scholar
  96. 96.
    Crescenzi O, Tomaselli S, Guerrini R, et al. Solution structure of the Alzheimer amyloid betapeptide (1–42) in an apolar microenvironment. Similarity with a virus fusion domain. Eur J Biochem 2002;269:5642–8.PubMedGoogle Scholar
  97. 97.
    Pike CJ, Overman MJ, Cotman CW. Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 1995;270:23895–8.PubMedGoogle Scholar
  98. 98.
    Teplow DB. Structural and kinetic features of amyloid beta-protein fibrillogenesis. Amyloid 1998;5:121–42.PubMedGoogle Scholar
  99. 99.
    Jarrett JT, Berger EP, Lansbury PT, Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 1993;32:4693–7.PubMedGoogle Scholar
  100. 100.
    Zou K, Kim D, Kakio A, et al. Amyloid beta-protein 1–40 protects neurons from damage induced by Abeta1–42 in culture and in rat brain. J Neurochem 2003;87:609–19.PubMedGoogle Scholar
  101. 101.
    Tamaoka A, Sawamura N, Odaka A, et al. Amyloid beta protein 1–42/43 (A beta 1–42/43) in cerebellar diffuse plaques: enzyme-linked immunosorbent assay and immunocytochemical study. Brain Res 1995;679:151–6.PubMedGoogle Scholar
  102. 102.
    Hosoda R, Saido TC, Otvos L, Jr., et al. Quantification of modified amyloid beta peptides in Alzheimer’s disease and Down syndrome brains. J Neuropathol Exp Neurol 1998;57:1089–95.PubMedGoogle Scholar
  103. 103.
    Houlden H, Baker M, McGowan E, et al. Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 2000;48:806–8.PubMedGoogle Scholar
  104. 104.
    Verdile G, Gnjec A, Miklossy J, et al. Protein markers for Alzheimer’s disease in the frontal cortex and cerebellum. Neurology 2004;63:1385–92.PubMedGoogle Scholar
  105. 105.
    Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer’s abeta by Cu[II] is induced by conditions representing physiological acidosis. J Biol Chem 1998;273:12817–26.PubMedGoogle Scholar
  106. 106.
    Miura T, Suzuki K, Kohata N, et al. Metal binding modes of Alzheimer’s amyloid beta-peptide in insoluble aggregates and soluble complexes. Biochemistry 2000;39:7024–31.PubMedGoogle Scholar
  107. 107.
    Gibson Wood W, Eckert GP, Igbavboa U, et al. Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer’s disease. Biochim Biophys Acta 2003;1610:281–90.PubMedGoogle Scholar
  108. 108.
    Avdulov NA, Chochina SV, Igbavboa U, et al. Lipid binding to amyloid beta-peptide aggregates: preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids. J Neurochem 1997;69:1746–52.PubMedGoogle Scholar
  109. 109.
    Michikawa M, Gong JS, Fan QW, et al. A novel action of Alzheimer’s amyloid beta-protein [Abeta]: oligomeric Abeta promotes lipid release. J Neurosci 2001;21:7226–35.PubMedGoogle Scholar
  110. 110.
    Tsui-Pierchala BA, Encinas M, Milbrandt J, et al. Lipid rafts in neuronal signaling and function. Trends Neurosci 2002;25:412–7.PubMedGoogle Scholar
  111. 111.
    Kakio A, Nishimoto S, Yanagisawa K, et al. Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 2002;41:7385–90.PubMedGoogle Scholar
  112. 112.
    Koudinov AR, Berezov TT, Koudinova NV. Alzheimer’s amyloid beta and lipid metabolism: a missing link? Faseb J 1998;12:1097–9.PubMedGoogle Scholar
  113. 113.
    Manelli AM, Stine WB, Van Eldik LJ, et al. ApoE and Abeta1–42 interactions: effects of isoform and conformation on structure and function. J Mol Neurosci 2004;23:235–46.PubMedGoogle Scholar
  114. 114.
    Holtzman DM, Bales KR, Wu S, et al. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest 1999;103:R15–R21.PubMedGoogle Scholar
  115. 115.
    Verdier Y, Zarandi M, Penke B. Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer’s disease. J Pept Sci 2004;10:229–48.PubMedGoogle Scholar
  116. 116.
    Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003;37:925–37.PubMedGoogle Scholar
  117. 117.
    Plant LD, Boyle JP, Smith IF, et al. The production of amyloid [beta] peptide is a critical requirement for the viability of central neurons. J Neurosci 2003;23:5531–5.PubMedGoogle Scholar
  118. 118.
    De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer’s disease. Brain Res Brain Res Rev 2000;33:1–12.PubMedGoogle Scholar
  119. 119.
    Lopez-Toledano MA, Shelanski ML. Neurogenic effect of ta-amyloid peptide in the development of neural stem cells. J Neurosci 2004;24:5439–44.Google Scholar
  120. 120.
    Haughey NJ, Liu D, Nath A, et al. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Med 2002;1:125–35.PubMedGoogle Scholar
  121. 121.
    Haughey NJ, Nath A, Chan SL, et al. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem 2002;83:1509–24.PubMedGoogle Scholar
  122. 122.
    Ramsden M, Plant LD, Webster NJ, et al. Differential effects of unaggregated and aggregated amyloid beta protein (1–40) on K( ) channel currents in primary cultures of rat cerebellar granule and cortical neurones. J Neurochem 2001;79: 699–712.PubMedGoogle Scholar
  123. 123.
    Crawford F, Suo Z, Fang C, et al. Characteristics of the in vitro vasoactivity of beta-amyloid peptides. Exp Neurol 1998;150:159–68.PubMedGoogle Scholar
  124. 124.
    Zou K, Gong J-S, Yanagisawa K, et al. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metalinduced oxidative damage. J Neurosci 2002;22: 4833–41.PubMedGoogle Scholar
  125. 125.
    Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 2000;39:6951–9.PubMedGoogle Scholar
  126. 126.
    Zhang L, Zhao B, Yew DT, et al. Processing of Alzheimer’s amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. Biochem Biophys Res Commun 1997;235:845–8.PubMedGoogle Scholar
  127. 127.
    Paola D, Domenicotti C, Nitti M, et al. Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 2000;268:642–6.PubMedGoogle Scholar
  128. 128.
    Cuajungco MP, Goldstein LE, Nunomura A, et al. Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 2000;275:19439–42.PubMedGoogle Scholar
  129. 129.
    Maynard CJ, Bush AI, Masters CL, et al. Metals and amyloid-beta in Alzheimer’s disease. Int J Exp Pathol 2005;86:147–59.PubMedGoogle Scholar
  130. 130.
    Pike CJ, Burdick D, Walencewicz AJ, et al. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 1993;13:1676–87.PubMedGoogle Scholar
  131. 131.
    Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 1990;250:279–82.PubMedGoogle Scholar
  132. 132.
    Roher AE, Ball MJ, Bhave SV, et al. Beta-amyloid from Alzheimer’s disease brains inhibits sprouting and survival of sympathetic neurons. Biochem Biophys Res Commun 1991;174:572–9.PubMedGoogle Scholar
  133. 133.
    Pike CJ, Walencewicz AJ, Glabe CG, et al. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 1991;563:311–4.PubMedGoogle Scholar
  134. 134.
    Mattson MP, Tomaselli KJ, Rydel RE. Calciumdestabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF. Brain Res 1993;621:35–49.PubMedGoogle Scholar
  135. 135.
    Mattson MP, Rydel RE. beta-Amyloid precursor protein and Alzheimer’s disease: the peptide plot thickens. Neurobiol Aging 1992;13:617–21.PubMedGoogle Scholar
  136. 136.
    Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A 1994;91: 12243–7.PubMedGoogle Scholar
  137. 137.
    Busciglio J, Lorenzo A, Yankner BA. Methodological variables in the assessment of beta amyloid neurotoxicity. Neurobiol Aging 1992;13:609–12.PubMedGoogle Scholar
  138. 138.
    Gong Y, Chang L, Viola KL, et al. Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 2003;100:10417–22.PubMedGoogle Scholar
  139. 139.
    Lacor PN, Buniel MC, Chang L, et al. Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 2004;24:10191–200.PubMedGoogle Scholar
  140. 140.
    Fan QW, Yu W, Senda T, et al. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem 2001;76:391–400.PubMedGoogle Scholar
  141. 141.
    Tong L, Thornton PL, Balazs R, et al. 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 2001;276:17301–6.PubMedGoogle Scholar
  142. 142.
    Zheng WH, Bastianetto S, Mennicken F, et al. Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience 2002;115:201–11.PubMedGoogle Scholar
  143. 143.
    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;25:563–8.PubMedGoogle Scholar
  144. 144.
    Yatin SM, Varadarajan S, Link CD, et al. In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1–42). Neurobiol Aging 1999;20:325–30; discussion 39-42.PubMedGoogle Scholar
  145. 145.
    Schubert D, Behl C, Lesley R, et al. Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad Sci U S A 1995;92:1989–93.PubMedGoogle Scholar
  146. 146.
    Mark RJ, Blanc EM, Mattson MP. Amyloid betapeptide and oxidative cellular injury in Alzheimer’s disease. Mol Neurobiol 1996;12:211–24.PubMedGoogle Scholar
  147. 147.
    Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004;304:448–52.PubMedGoogle Scholar
  148. 148.
    Butterfield DA. Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 2002;36:1307–13.Google Scholar
  149. 149.
    Huang X, Atwood CS, Hartshorn MA, et al. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 1999;38:7609–16.PubMedGoogle Scholar
  150. 150.
    Opazo C, Huang X, Cherny RA, et al. Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem 2002;277:40302–8.PubMedGoogle Scholar
  151. 151.
    Selkoe DJ. Clearing the brain’s amyloid cobwebs. Neuron 2001;32:177–80.PubMedGoogle Scholar
  152. 152.
    Zlokovic BV. Clearing amyloid through the bloodbrain barrier. J Neurochem 2004;89:807–11.PubMedGoogle Scholar
  153. 153.
    Eckman EA, Reed DK, Eckman CB. Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem 2001;276:24540–8.PubMedGoogle Scholar
  154. 154.
    Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Abeta1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000;6:143–50.PubMedGoogle Scholar
  155. 155.
    Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998;273:32730–8.PubMedGoogle Scholar
  156. 156.
    Tucker HM, Kihiko M, Caldwell JN, et al. The plasmin system is induced by and degrades amyloidbeta aggregates. J Neurosci 2000;20:3937–46.PubMedGoogle Scholar
  157. 157.
    Sudoh S, Frosch MP, Wolf BA. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and-insoluble pools in CHO-695 cells. Biochemistry 2002;41:1091–9.PubMedGoogle Scholar
  158. 158.
    Morelli L, Llovera R, Gonzalez SA, et al. Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. J Biol Chem 2003;278:23221–6.PubMedGoogle Scholar
  159. 159.
    Turner AJ, Murphy LJ. Molecular pharmacology of endothelin converting enzymes. Biochem Pharmacol 1996;51:91–102.PubMedGoogle Scholar
  160. 160.
    Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Abeta by neprilysin. Science 2001;292:1550–2.PubMedGoogle Scholar
  161. 161.
    Yasojima K, McGeer EG, McGeer PL. Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer’s disease and normal brain. Brain Res 2001;919:115–21.PubMedGoogle Scholar
  162. 162.
    Wang DS, Lipton RB, Katz MJ, et al. Decreased neprilysin immunoreactivity in Alzheimer’s disease, but not in pathological aging. J Neuropathol Exp Neurol 2005;64:378–85.PubMedGoogle Scholar
  163. 163.
    Weller RO. Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer’s disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 1998;57:885–94.PubMedGoogle Scholar
  164. 164.
    Lauer D, Reichenbach A, Birkenmeier G. Alpha 2-macroglobulin-mediated degradation of amyloid beta 1–42: a mechanism to enhance amyloid beta catabolism. Exp Neurol 2001;167:385–92.PubMedGoogle Scholar
  165. 165.
    Qiu Z, Strickland DK, Hyman BT, et al. Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. J Neurochem 1999;73:1393–8.PubMedGoogle Scholar
  166. 166.
    Shaffer LM, Dority MD, Gupta-Bansal R, et al. Amyloid beta protein (A beta) removal by neuroglial cells in culture. Neurobiol Aging 1995;16:737–45.PubMedGoogle Scholar
  167. 167.
    Kakimura J, Kitamura Y, Taniguchi T, et al. Bip/GRP78-induced production of cytokines and uptake of amyloid-beta(1–42) peptide in microglia. Biochem Biophys Res Commun 2001;281:6–10.PubMedGoogle Scholar
  168. 168.
    Banks WA, Ronbinson SM, Verma S, et al. Efflux of human and mouse amyloid β proteins 1–40 and 1–42 from brain: impairment in a mouse model of Alzheimer’s disease. Neuroscience 2003;121:487–92.PubMedGoogle Scholar
  169. 169.
    Iwatsubo T, Mann DM, Odaka A, et al. Amyloid beta protein (A beta) deposition: a beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 1995;37:294–9.PubMedGoogle Scholar
  170. 170.
    Calero M, Rostagno A, Matsubara E, et al. Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc Res Tech 2000;50:305–15.PubMedGoogle Scholar
  171. 171.
    Pollack SJ, Lewis H. Secretase inhibitors for Alzheimer’s disease: challenges of a promiscuous protease. Curr Opin Investig Drugs 2005;6:35–47.PubMedGoogle Scholar
  172. 172.
    Doraiswamy PM, Finefrock AE. Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol 2004;3:431–4.PubMedGoogle Scholar
  173. 173.
    Lahiri DK, Farlow MR, Sambamurti K, et al. A critical analysis of new molecular targets and strategies for drug developments in Alzheimer’s disease. Curr Drug Targets 2003;4:97–112.PubMedGoogle Scholar
  174. 174.
    Pietrzik C, Behl C. Concepts for the treatment of Alzheimer’s disease: molecular mechanisms and clinical application. Int J Exp Pathol 2005;86:173–85.Google Scholar
  175. 175.
    Cumming JN, Iserloh U, Kennedy ME. Design and development of BACE-1 inhibitors. Curr Opin Drug Discov Devel 2004;7:536–56.PubMedGoogle Scholar
  176. 176.
    Kobayashi DT, Chen KS. Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav 2005;4:173–96.PubMedGoogle Scholar
  177. 177.
    Anderson JJ, Holtz G, Baskin PP, et al. Reductions in beta-amyloid concentrations in vivo by the gammasecretase inhibitors BMS-289948 and BMS-299897. Biochem Pharmacol 2005;69:689–98.PubMedGoogle Scholar
  178. 178.
    Barten DM, Guss VL, Corsa JA, et al. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther 2005;312:635–43.PubMedGoogle Scholar
  179. 179.
    Siemers E, Skinner M, Dean RA, et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28:126–32.PubMedGoogle Scholar
  180. 180.
    Cherny RA, Legg JT, McLean CA, et al. Aqueous dissolution of Alzheimer’s disease Abeta amyloid deposits by biometal depletion. J Biol Chem 1999;274:23223–8.PubMedGoogle Scholar
  181. 181.
    Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001;30:665–76.PubMedGoogle Scholar
  182. 182.
    Ritchie CW, Bush AI, Mackinnon A, et al. Metalprotein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer’s disease: a pilot phase 2 clinical trial. Arch Neurol 2003;60:1685–91.PubMedGoogle Scholar
  183. 183.
    DeMattos RB, Bales KR, Cummins DJ, et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2001;98:8850–5.PubMedGoogle Scholar
  184. 184.
    Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-diseaselike pathology in the PDAPP mouse. Nature 1999;400:173–7.PubMedGoogle Scholar
  185. 185.
    Gotz J, Streffer JR, David D, et al. Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry 2004;9:664–83.PubMedGoogle Scholar
  186. 186.
    Weiner HL, Lemere CA, Maron R, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 2000;48:567–79.PubMedGoogle Scholar
  187. 187.
    Sigurdsson EM, Scholtzova H, Mehta PD, et al. Immunization with a nontoxic/nonfibrillar amyloidbeta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 2001;159:439–47.PubMedGoogle Scholar
  188. 188.
    Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat Med 2000;6:916–9.PubMedGoogle Scholar
  189. 189.
    Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46–54.PubMedGoogle Scholar
  190. 190.
    Das P, Golde TE. Open peer commentary regarding Abeta immunization and CNS inflammation by Pasinetti et al. Neurobiol Aging 2002;23:671–4; discussion 83-4.PubMedGoogle Scholar
  191. 191.
    Sigurdsson E, Wisniewski, T., Frangione, B. Infectivity of amyloid diseases. Trends Mol Med 2002.Google Scholar
  192. 192.
    Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer’s disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003.Google Scholar
  193. 193.
    Hock C, Konietzko U, Streffer JR, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–54.PubMedGoogle Scholar
  194. 194.
    Chauhan NB, Siegel GJ. Efficacy of anti-Abeta antibody isotypes used for intracerebroventricular immunization in TgCRND8. Neurosci Lett 2005;375:143–7.PubMedGoogle Scholar
  195. 195.
    Li SB, Wang HQ, Lin X, et al. Specific humoral immune responses in rhesus monkeys vaccinated with the Alzheimer’s disease-associated beta-amyloid 1–15 peptide vaccine. Chin Med J (Engl) 2005;118:660–4.Google Scholar
  196. 196.
    Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003;327:128.PubMedGoogle Scholar
  197. 197.
    Szekely CA, Thorne JE, Zandi PP, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology 2004;23:159–69.PubMedGoogle Scholar
  198. 198.
    Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212–6.PubMedGoogle Scholar
  199. 199.
    Weggen S, Eriksen JL, Sagi SA, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem 2003;278:31831–7.PubMedGoogle Scholar
  200. 200.
    Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer’s disease progression: a randomized controlled trial. JAMA 2003;289:2819–26.PubMedGoogle Scholar
  201. 201.
    Cole GM, Morihara T, Lim GP, et al. NSAID and antioxidant prevention of Alzheimer’s disease: lessons from in vitro and animal models. Ann N Y Acad Sci 2004;1035:68–84.PubMedGoogle Scholar
  202. 202.
    Lehmann JM, Kliewer SA, Moore LB, et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997;272:3137–40.PubMedGoogle Scholar
  203. 203.
    Jaradat MS, Wongsud B, Phornchirasilp S, et al. Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. Biochem Pharmacol 2001;62:1587–95.PubMedGoogle Scholar
  204. 204.
    Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391:82–6.PubMedGoogle Scholar
  205. 205.
    Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79–82.PubMedGoogle Scholar
  206. 206.
    Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1–42 levels in APPV717I transgenic mice. Brain 2005;128:1442–53.PubMedGoogle Scholar
  207. 207.
    Wolozin B. Cholesterol and Alzheimer’s disease. Biochem Soc Trans 2002;30:525–9.PubMedGoogle Scholar
  208. 208.
    Refolo LM, Malester B, LaFrancois J, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 2000;7:321–31.PubMedGoogle Scholar
  209. 209.
    Refolo LM, Pappolla MA, LaFrancois J, et al. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 2001;8:890–9.PubMedGoogle Scholar
  210. 210.
    Sidera C, Parsons R, Austen B. The regulation of beta-secretase by cholesterol and statins in Alzheimer’s disease. J Neurol Sci 2005;229–230:269–73.PubMedGoogle Scholar
  211. 211.
    Stuve O, Youssef S, Steinman L, et al. Statins as potential therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol 2003;16:393–401.PubMedGoogle Scholar
  212. 212.
    Sjogren M, Gustafsson K, Syversen S, et al. Treatment with simvastatin in patients with Alzheimer’s disease lowers both alpha-and betacleaved amyloid precursor protein. Dement Geriatr Cogn Disord 2003;16:25–30.PubMedGoogle Scholar
  213. 213.
    Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-tomoderate AD. Curr Alzheimer Res 2005;2:343–53.PubMedGoogle Scholar
  214. 214.
    Rea TD, Breitner JC, Psaty BM, et al. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol 2005;62:1047–51.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2007

Authors and Affiliations

  • Gillian C. Gregory
    • 1
  • Claire E. Shepherd
    • 1
  • Glenda M. Halliday
    • 2
  1. 1.Prince of Wales Medical Research InstituteUniversity of New South WalesSydneyAustralia
  2. 2.University of New South WalesPrince of Wales Medical Research InstituteRanwick SydneyAustralia

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