Advertisement

Synapses and Alzheimers’s Disease: Effect of Immunotherapy?

  • Nathan C. Denham
  • James A. R. Nicoll
  • Delphine Boche
Chapter

Abstract

Alzheimer’s disease (AD) was first described more than 100 years ago; however, the mechanisms underlying its pathogenesis are still poorly understood. Current theories suggest a pivotal role for the protein amyloid-β (Aβ) and many of the novel treatments for AD focus on Aβ. In this chapter, we discuss evidence that Aβ underpins the cognitive decline as a result of direct and indirect toxicity of the peptide on synapses in the cerebral cortex and hippocampus. Furthermore, we will follow the promise that Aβ immunisation holds to alter the natural history of AD, from its beginnings in animal models to the current research on humans. The success seen in mice in preventing both synapse loss and reducing functional decline is yet to be matched in humans and serious adverse events in patients stopped the initial vaccination approach. Research, however, is continuing in human AD aiming to provide a greater understanding of the mechanisms underlying the immune response and the potential effects of immunisation on preventing or reversing cognitive impairment.

Keywords

Long Term Potentiation Cerebral Amyloid Angiopathy Dystrophic Neurites Synaptic Loss Synaptic Density 
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.

References

  1. Albert M S (1996). Cognitive and neurobiologic markers of early Alzheimer disease. Proc Natl Acad Sci U S A 93:13547–51PubMedGoogle Scholar
  2. Almeida C G, Tampellini D, Takahashi R H, et al. (2005). Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–98PubMedGoogle Scholar
  3. Arriagada P V, Marzloff K and Hyman B T (1992). Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–8PubMedGoogle Scholar
  4. Association A P (2000). Diagnostic and Statistical Manual of Mental Disorders, Washington, DCGoogle Scholar
  5. Bahmanyar S, Higgins G A, Goldgaber D, et al. (1987). Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer’s disease. Science 237:77–80PubMedGoogle Scholar
  6. Bard F, Barbour R, Cannon C, et al. (2003). Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A 100:2023–8PubMedGoogle Scholar
  7. Bard F, Cannon C, Barbour R, et al. (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–9PubMedGoogle Scholar
  8. Bayer A J, Bullock R, Jones R W, et al. (2005). Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64:94–101PubMedGoogle Scholar
  9. Boche D, Zotova E, Weller R O, et al. (2008). Consequence of A{beta} immunization on the vasculature of human Alzheimer’s disease brain. Brain 131:3299–310PubMedGoogle Scholar
  10. Bombois S, Maurage C A, Gompel M, et al. (2007). Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol 64:583–7PubMedGoogle Scholar
  11. Borchelt D R, Ratovitski T, van Lare J, et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–45PubMedGoogle Scholar
  12. Braak H and Braak E (1995). Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–8; discussion 278–84PubMedGoogle Scholar
  13. Braak H, Braak E, Bohl J, et al. (1996). Age, neurofibrillary changes, A beta-amyloid and the onset of Alzheimer’s disease. Neurosci Lett 210:87–90PubMedGoogle Scholar
  14. Brown M S and Goldstein J L (1986). A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47PubMedGoogle Scholar
  15. Buttini M, Masliah E, Barbour R, et al. (2005). Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci 25:9096–101PubMedGoogle Scholar
  16. Chartier-Harlin M C, Crawford F, Houlden H, et al. (1991). Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–6PubMedGoogle Scholar
  17. Chauhan N B (2003). Membrane dynamics, cholesterol homeostasis, and Alzheimer’s disease. J Lipid Res 44:2019–29PubMedGoogle Scholar
  18. Citron M, Westaway D, Xia W, et al. (1997). Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67–72PubMedGoogle Scholar
  19. Davies C A, Mann D M, Sumpter P Q, et al. (1987). A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78:151–64PubMedGoogle Scholar
  20. de la Monte S M and Hedley-Whyte E T (1990). Small cerebral hemispheres in adults with Down’s syndrome: contributions of developmental arrest and lesions of Alzheimer’s disease. J Neuropathol Exp Neurol 49:509–20PubMedGoogle Scholar
  21. DeMattos R B, Bales K R, Cummins D J, et al. (2001). 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 98:8850–5PubMedGoogle Scholar
  22. Duff K, Eckman C, Zehr C, et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–3PubMedGoogle Scholar
  23. Elgersma Y and Silva A J (1999). Molecular mechanisms of synaptic plasticity and memory. Curr Opin Neurobiol 9:209–13PubMedGoogle Scholar
  24. Ferrer I, Boada Rovira M, Sanchez Guerra M L, et al. (2004). Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20PubMedGoogle Scholar
  25. Games D, Adams D, Alessandrini R, et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–7PubMedGoogle Scholar
  26. Games D, Bard F, Grajeda H, et al. (2000). Prevention and reduction of AD-type pathology in PDAPP mice immunized with A beta 1–42. Ann N Y Acad Sci 920:274–84PubMedGoogle Scholar
  27. Giedraitis V, Sundelof J, Irizarry M C, et al. (2007). The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer’s disease. Neurosci Lett 427:127–31PubMedGoogle Scholar
  28. Gilman S, Koller M, Black R S, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–62PubMedGoogle Scholar
  29. Goate A, Chartier-Harlin M C, Mullan M, et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–6PubMedGoogle Scholar
  30. Goedert M, Crowther R A and Spillantini M G (1998). Tau mutations cause frontotemporal dementias. Neuron 21:955–8PubMedGoogle Scholar
  31. Graham D I and Lantos P L (2002). Greenfield’s Neuropathology. London, ArnoldGoogle Scholar
  32. Grimm M O, Grimm H S, Patzold A J, et al. (2005). Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol 7:1118–23PubMedGoogle Scholar
  33. Haass C and Selkoe D J (1993). Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75:1039–42PubMedGoogle Scholar
  34. Hardy J, Duff K, Hardy K G, et al. (1998). Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1:355–8PubMedGoogle Scholar
  35. Hardy J and Selkoe D J (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–6PubMedGoogle Scholar
  36. Hardy J A and Higgins G A (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–5PubMedGoogle Scholar
  37. Hartley D M, Walsh D M, Ye C P, et al. (1999). Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–84PubMedGoogle Scholar
  38. Hock C, Konietzko U, Streffer J R, et al. (2003). Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 38:547–54PubMedGoogle Scholar
  39. Holcomb L, Gordon M N, McGowan E, et al. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100PubMedGoogle Scholar
  40. Holmes C, Boche D, Wilkinson D, et al. (2008). Long term effect of Abeta42 immunization in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–23PubMedGoogle Scholar
  41. Hsia A Y, Masliah E, McConlogue L, et al. (1999). Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 96:3228–33PubMedGoogle Scholar
  42. Hsiao K, Chapman P, Nilsen S, et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedGoogle Scholar
  43. Jacobsen J S, Wu C C, Redwine J M, et al. (2006). Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 103:5161–6PubMedGoogle Scholar
  44. Janus C, Pearson J, McLaurin J, et al. (2000). Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–82PubMedGoogle Scholar
  45. Kang J, Lemaire H G, Unterbeck A, et al. (1987). The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–6PubMedGoogle Scholar
  46. Klyubin I, Betts V, Welzel A T, et al. (2008). Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. J Neurosci 28:4231–7PubMedGoogle Scholar
  47. Lai, M K, Tsang S W, Garcia-Alloza, M, et al. (2006). Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer’s disease. Neurobiol Dis 22(3): 555–561Google Scholar
  48. Lassmann H (1996). Patterns of synaptic and nerve cell pathology in Alzheimer’s disease. Behav Brain Res 78:9–14PubMedGoogle Scholar
  49. Lassmann H, Fischer P and Jellinger K (1993). Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci 695:59–64PubMedGoogle Scholar
  50. Lee H G, Zhu X, Castellani R J, et al. (2007). Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321:823–9PubMedGoogle Scholar
  51. Lee M, Bard F, Johnson-Wood K, et al. (2005). Abeta42 immunization in Alzheimer’s disease generates Abeta N-terminal antibodies. Ann Neurol 58:430–5PubMedGoogle Scholar
  52. Levy-Lahad E, Wasco W, Poorkaj P, et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–7PubMedGoogle Scholar
  53. Lewis J, Dickson D W, Lin W L, et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–91PubMedGoogle Scholar
  54. Love S, Siew L K, Dawbarn D, et al. (2006). Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 27:797–803PubMedGoogle Scholar
  55. Lue L F, Kuo Y M, Roher A E, et al. (1999). Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–62PubMedGoogle Scholar
  56. Luscher C, Nicoll R A, Malenka R C, et al. (2000). Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat Neurosci 3:545–50PubMedGoogle Scholar
  57. Mahley R W (1988). Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240:622–30PubMedGoogle Scholar
  58. Mann D M, Iwatsubo T, Ihara Y, et al. (1996). Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 148:1257–66PubMedGoogle Scholar
  59. Martin S J, Grimwood P D and Morris R G (2000). Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23:649–711PubMedGoogle Scholar
  60. Masliah E (1995). Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–19PubMedGoogle Scholar
  61. Masliah E, Hansen L, Adame A, et al. (2005). Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–31PubMedGoogle Scholar
  62. Masliah E, Mallory M, Alford M, et al. (2001). Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–9PubMedGoogle Scholar
  63. Masliah E, Terry R D, Alford M, et al. (1991). Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 138:235–46PubMedGoogle Scholar
  64. McLaurin J, Cecal R, Kierstead M E, et al. (2002). Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8:1263–9PubMedGoogle Scholar
  65. Morgan D, Diamond D M, Gottschall P E, et al. (2000). A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–5PubMedGoogle Scholar
  66. Mucke L, Masliah E, Yu G Q, et al. (2000). High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–8PubMedGoogle Scholar
  67. Myers A, Holmans P, Marshall H, et al. (2000). Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 290:2304–5PubMedGoogle Scholar
  68. Nagy Z, Esiri M M, Jobst K A, et al. (1995). Relative roles of plaques and tangles in the dementia of Alzheimer’s disease: correlations using three sets of neuropathological criteria. Dementia 6:21–31PubMedGoogle Scholar
  69. Naslund J, Haroutunian V, Mohs R, et al. (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–7PubMedGoogle Scholar
  70. Nicoll J A, Barton E, Boche D, et al. (2006). Abeta Species Removal After Abeta42 Immunization. J Neuropathol Exp Neurol 65:1040–1048PubMedGoogle Scholar
  71. Nicoll J A, Wilkinson D, Holmes C, et al. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–52PubMedGoogle Scholar
  72. Oddo S, Billings L, Kesslak J P, et al. (2004). Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–32PubMedGoogle Scholar
  73. Oddo S, Caccamo A, Kitazawa M, et al. (2003a). Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–70PubMedGoogle Scholar
  74. Oddo S, Caccamo A, Shepherd J D, et al. (2003b). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–21PubMedGoogle Scholar
  75. Orgogozo J M, Gilman S, Dartigues J F, et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46–54PubMedGoogle Scholar
  76. Oyama F, Cairns N J, Shimada H, et al. (1994). Down’s syndrome: up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem 62:1062–6PubMedGoogle Scholar
  77. Poirier J (2000). Apolipoprotein E and Alzheimer’s disease. A role in amyloid catabolism. Ann N Y Acad Sci 924:81–90PubMedGoogle Scholar
  78. Price J L and Morris J C (1999). Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–68PubMedGoogle Scholar
  79. Riddell D R, Zhou H, Atchison K, et al. (2008). Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 28:11445–53PubMedGoogle Scholar
  80. Ritchie K and Lovestone S (2002). The dementias. Lancet 360:1759–66PubMedGoogle Scholar
  81. Roman F S, Truchet B, Marchetti E, et al. (1999). Correlations between electrophysiological observations of synaptic plasticity modifications and behavioral performance in mammals. Prog Neurobiol 58:61–87PubMedGoogle Scholar
  82. Saunders A M, Strittmatter W J, Schmechel D, et al. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–72PubMedGoogle Scholar
  83. Schenk D, Barbour R, Dunn W, et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–7PubMedGoogle Scholar
  84. Schenk D, Hagen M and Seubert P (2004). Current progress in beta-amyloid immunotherapy. Curr Opin Immunol 16:599–606PubMedGoogle Scholar
  85. Scheuner D, Eckman C, Jensen M, 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. Nat Med 2:864–70PubMedGoogle Scholar
  86. Selkoe D J (1991). The molecular pathology of Alzheimer’s disease. Neuron 6:487–98PubMedGoogle Scholar
  87. Selkoe D J (2001). Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–66PubMedGoogle Scholar
  88. Selkoe D J (2002). Alzheimer’s disease is a synaptic failure. Science 298:789–91PubMedGoogle Scholar
  89. Shankar G M, Bloodgood B L, Townsend M, et al. (2007). Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–75PubMedGoogle Scholar
  90. Shankar G M, Li S, Mehta T H, et al. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–42PubMedGoogle Scholar
  91. Sherrington R, Rogaev E I, Liang Y, et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–60PubMedGoogle Scholar
  92. Small D H, Mok S S and Bornstein J C (2001). Alzheimer’s disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2:595–8PubMedGoogle Scholar
  93. Small G W, Rabins P V, Barry P P, et al. (1997). Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 278:1363–71PubMedGoogle Scholar
  94. Small S A and Duff K (2008). Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–42PubMedGoogle Scholar
  95. Snyder E M, Nong Y, Almeida C G, et al. (2005). Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–8PubMedGoogle Scholar
  96. Solomon B, Koppel R, Frankel D, et al. (1997). Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A 94:4109–12PubMedGoogle Scholar
  97. Solomon B, Koppel R, Hanan E, et al. (1996). Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 93:452–5PubMedGoogle Scholar
  98. Spillantini M G and Goedert M (1998). Tau protein pathology in neurodegenerative diseases. Trends Neurosci 21:428–33PubMedGoogle Scholar
  99. St George-Hyslop P H and Morris J C (2008). Will anti-amyloid therapies work for Alzheimer’s disease? Lancet 372:180–2PubMedGoogle Scholar
  100. St George-Hyslop P H, Tanzi R E, Polinsky R J, et al. (1987). The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235:885–90PubMedGoogle Scholar
  101. Strittmatter W J, Saunders A M, Schmechel D, et al. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977–81PubMedGoogle Scholar
  102. Sze C I, Troncoso J C, Kawas C, et al. (1997). Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–44PubMedGoogle Scholar
  103. Terry R D (1996). The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol 55:1023–5PubMedGoogle Scholar
  104. Terry R D, Masliah E, Salmon D P, et al. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–80PubMedGoogle Scholar
  105. Uylings H B and de Brabander J M (2002). Neuronal changes in normal human aging and Alzheimer’s disease. Brain Cogn 49:268–76PubMedGoogle Scholar
  106. Varadarajan S, Kanski J, Aksenova M, et al. (2001). Different mechanisms of oxidative stress and neurotoxicity for Alzheimer’s A beta(1–42) and A beta(25–35). J Am Chem Soc 123:5625–31PubMedGoogle Scholar
  107. Varadarajan S, Yatin S, Kanski J, et al. (1999). Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 50:133–41PubMedGoogle Scholar
  108. Walsh D M, Klyubin I, Fadeeva J V, et al. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–9PubMedGoogle Scholar
  109. Wang H W, Pasternak J F, Kuo H, et al. (2002). Soluble oligomers of beta amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 924:133–40PubMedGoogle Scholar
  110. Wavrant-DeVrieze F, Lambert J C, Stas L, et al. (1999). Association between coding variability in the LRP gene and the risk of late-onset Alzheimer’s disease. Hum Genet 104:432–4PubMedGoogle Scholar
  111. Weller R O and Nicoll J A (2003). Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain. Neurol Res 25:611–6PubMedGoogle Scholar
  112. Weller R O, Subash M, Preston S D, et al. (2008). Perivascular drainage of amyloid from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–66PubMedGoogle Scholar
  113. Wilcock D M, DiCarlo G, Henderson D, et al. (2003). Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23:3745–51PubMedGoogle Scholar
  114. Wilcock D M, Munireddy S K, Rosenthal A, et al. (2004). Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15:11–20PubMedGoogle Scholar
  115. Wisniewski K E, Wisniewski H M and Wen G Y (1985). Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17:278–82PubMedGoogle Scholar
  116. Yatin S M, Varadarajan S, Link C D, et al. (1999). In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1–42). Neurobiol Aging 20: 325–30; discussion 339–42PubMedGoogle Scholar
  117. Ye C P, Selkoe D J and Hartley D M (2003). Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocortical cultures. Neurobiol Dis 13:177–90PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Nathan C. Denham
  • James A. R. Nicoll
  • Delphine Boche
    • 1
  1. 1.Division of Clinical NeurosciencesUniversity of SouthamptonSouthamptonUK

Personalised recommendations