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01-09-2010 | Review

Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis

Authors: Delphine Boche, Nathan Denham, Clive Holmes, James A. R. Nicoll

Published in: Acta Neuropathologica | Issue 3/2010

Abstract

The amyloid cascade hypothesis of Alzheimer’s disease (AD) is testable: it implies that interference with Aβ aggregation and plaque formation may be therapeutically useful. Aβ42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Aβ immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Aβ immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Aβ immunisation trial. In immunised AD patients, we found: a lower Aβ load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological “side effects” including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Aβ. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Aβ immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.

Agadjanyan MG, Ghochikyan A, Petrushina I et al (2005) Prototype Alzheimer’s disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol 174:1580–1586PubMed

Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421PubMedCrossRef

Alaupovic P (1982) The role of apolipoproteins in lipid transport processes. Ric Clin Lab 12:3–21PubMed

Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129PubMedCrossRef

Asuni AA, Boutajangout A, Scholtzova H et al (2006) Vaccination of Alzheimer’s model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci 24:2530–2542PubMedCrossRef

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 USA 100:2023–2028PubMedCrossRef

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 6:916–919PubMedCrossRef

Bayer AJ, Bullock R, Jones RW et al (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64:94–101PubMed

Boche D, Donald J, Love S et al (2010) Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol 120:13–20PubMedCrossRef

10.

Boche D, Nicoll JA (2008) The role of the immune system in clearance of abeta from the brain. Brain Pathol 18:267–278PubMedCrossRef

11.

Boche D, Zotova E, Weller RO et al (2008) Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain 131:3299–3310PubMedCrossRef

12.

Bombois S, Maurage CA, Gompel M et al (2007) Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol 64:583–587PubMedCrossRef

13.

Borchelt DR, 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 19:939–945PubMedCrossRef

14.

Boyles JK, Zoellner CD, Anderson LJ et al (1989) A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest 83:1015–1031PubMedCrossRef

15.

Brendza RP, Bacskai BJ, Cirrito JR et al (2005) Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 115:428–433PubMed

16.

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 25:9096–9101PubMedCrossRef

17.

Carare RO, Bernardes-Silva M, Newman TA et al (2008) Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131–144PubMedCrossRef

18.

Chauhan NB (2003) Membrane dynamics, cholesterol homeostasis, and Alzheimer’s disease. J Lipid Res 44:2019–2029PubMedCrossRef

19.

Clapham R, O’Sullivan E, Weller RO, Carare RO (2010) Cervical lymph nodes are found in direct relationship with the internal carotid artery: significance for the lymphatic drainage of the brain. Clin Anat 23:43–47PubMed

20.

Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913PubMedCrossRef

21.

Davies CA, Mann DM, Sumpter PQ, Yates PO (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 78:151–164PubMedCrossRef

22.

DeMattos RB, Bales KR, Cummins DJ 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 USA 98:8850–8855PubMedCrossRef

23.

DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267PubMedCrossRef

24.

DeMattos RB, Bales KR, Parsadanian M et al (2002) Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer’s disease. J Neurochem 81:229–236PubMedCrossRef

25.

Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM (2004) Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 55:250–256PubMedCrossRef

26.

Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20PubMedCrossRef

27.

Fidani L, Rooke K, Chartier-Harlin MC et al (1992) Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer’s disease: identification of a further family with APP717 Val→Ile. Hum Mol Genet 1:165–168PubMedCrossRef

28.

Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198PubMedCrossRef

29.

Games D, Adams D, Alessandrini R et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527PubMedCrossRef

30.

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 920:274–284PubMedCrossRef

31.

Gentleman SM, Leclercq PD, Moyes L et al (2004) Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci Int 146:97–104PubMedCrossRef

32.

Gilman S, Koller M, Black RS et al (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562PubMedCrossRef

33.

Gong Y, Chang L, Viola KL et al (2003) Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 100:10417–10422PubMedCrossRef

34.

Greenberg SM (1998) Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51:690–694PubMed

35.

Griffin WS (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 83:470S–474SPubMed

36.

Griffin WS, Sheng JG, Royston MC et al (1998) Glial-neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 8:65–72PubMedCrossRef

37.

Haltia M, Viitanen M, Sulkava R et al (1994) Chromosome 14-encoded Alzheimer’s disease: genetic and clinicopathological description. Ann Neurol 36:362–367PubMedCrossRef

38.

Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388PubMedCrossRef

39.

Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRef

40.

Heston LL, Mastri AR (1977) The genetics of Alzheimer’s disease: associations with hematologic malignancy and Down’s syndrome. Arch Gen Psychiatry 34:976–981PubMed

41.

Hock C, Konietzko U, Streffer JR et al (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 38:547–554PubMedCrossRef

42.

Holcomb L, Gordon MN, McGowan E et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100PubMedCrossRef

43.

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 372:216–223PubMedCrossRef

44.

Holtzman DM, Bales KR, Wu S et al (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15–R21PubMedCrossRef

45.

Hsiao K, Chapman P, Nilsen S et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRef

46.

Istrin G, Bosis E, Solomon B (2006) Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res 84:434–443PubMedCrossRef

47.

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 408:979–982PubMedCrossRef

48.

Kalaria RN (1999) Microglia and Alzheimer’s disease. Curr Opin Hematol 6:15–24PubMedCrossRef

49.

Karlinsky H, Vaula G, Haines JL et al (1992) Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer’s disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene. Neurology 42:1445–1453PubMed

50.

Kim HD, Cao Y, Kong FK et al (2005) Induction of a Th2 immune response by co-administration of recombinant adenovirus vectors encoding amyloid beta-protein and GM-CSF. Vaccine 23:2977–2986PubMedCrossRef

51.

Korwek KM, Trotter JH, Ladu MJ, Sullivan PM, Weeber EJ (2009) ApoE isoform-dependent changes in hippocampal synaptic function. Mol Neurodegener 4:21PubMedCrossRef

52.

Krugers HJ, Mulder M, Korf J et al (1997) Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E deficient mice. Neuroreport 8:2505–2510PubMedCrossRef

53.

Lassmann H (1996) Patterns of synaptic and nerve cell pathology in Alzheimer’s disease. Behav Brain Res 78:9–14PubMedCrossRef

54.

Lee SJ, Liyanage U, Bickel PE et al (1998) A detergent-insoluble membrane compartment contains A beta in vivo. Nat Med 4:730–734PubMedCrossRef

55.

Lemere CA, Masliah E (2010) Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 6:108–119PubMedCrossRef

56.

Lemere CA, Spooner ET, LaFrancois J et al (2003) Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis 14:10–18PubMedCrossRef

57.

Levi O, Lutjohann D, Devir A et al (2005) Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation. J Neurochem 95:987–997PubMedCrossRef

58.

Lombardo JA, Stern EA, McLellan ME et al (2003) Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci 23:10879–10883PubMed

59.

Lowe J, Mirra SS, Hyman BT, Dickson DW (2008) Ageing and dementia. In: Love S, Louis DN, Ellison DW (eds) Greenfield’s neuropathology, 8th edn. Edward Arnold Ltd, London, pp 1031–1152

60.

Manea M, Mezo G, Hudecz F, Przybylski M (2004) Polypeptide conjugates comprising a beta-amyloid plaque-specific epitope as new vaccine structures against Alzheimer’s disease. Biopolymers 76:503–511PubMedCrossRef

61.

Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–519PubMed

62.

Masliah E, Hansen L, Adame A et al (2005) Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–131PubMed

63.

Masliah E, Terry RD, Alford M, DeTeresa R, Hansen LA (1991) Cortical and subcortical patterns of synaptophysin like immunoreactivity in Alzheimer’s disease. Am J Pathol 138:235–246PubMed

64.

Mauch DH, Nagler K, Schumacher S et al (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357PubMedCrossRef

65.

McDonald JM, Savva GM, Brayne C et al (2010) The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain 133:1328–1341CrossRef

66.

McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200PubMedCrossRef

67.

McLaurin J, Cecal R, Kierstead ME et al (2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8:1263–1269PubMedCrossRef

68.

Morgan D, Diamond DM, Gottschall PE et al (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985PubMedCrossRef

69.

Mouri A, Noda Y, Hara H et al (2007) Oral vaccination with a viral vector containing Abeta cDNA attenuates age-related Abeta accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. FASEB J 21:2135–2148PubMedCrossRef

70.

Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354PubMedCrossRef

71.

Mullan M, Crawford F, Axelman K et al (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1:345–347PubMedCrossRef

72.

Mullan M, Houlden H, Windelspecht M et al (1992) A locus for familial early-onset Alzheimer’s disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene. Nat Genet 2:340–342PubMedCrossRef

73.

Naruse S, Igarashi S, Kobayashi H et al (1991) Mis-sense mutation Val–Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer’s disease. Lancet 337:978–979PubMedCrossRef

74.

Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14PubMedCrossRef

75.

Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW (2009) Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimer’s Dement 5:287–294CrossRef

76.

Nicoll JA, Barton E, Boche D et al (2006) Abeta species removal after Abeta42 immunization. J Neuropathol Exp Neurol 65:1040–1048PubMedCrossRef

77.

Nicoll JA, McCarron MO (2001) APOE gene polymorphism as a risk factor for cerebral amyloid angiopathy-related hemorrhage. Amyloid 8(Suppl 1):51–55PubMed

78.

Nicoll JA, Wilkinson D, Holmes C et al (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452PubMedCrossRef

79.

Nicoll JA, Yamada M, Frackowiak J, Mazur-Kolecka B, Weller RO (2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25:589–597 (discussion 603–604)PubMedCrossRef

80.

Nwosu I, Gairhe S, Struble RG, Nathan BP (2008) Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb. Neurosci Lett 441:282–285PubMedCrossRef

81.

Oddo S, Vasilevko V, Caccamo A et al (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 281:39413–39423PubMedCrossRef

82.

Oh JY, Nam YJ, Jo A et al (2010) Apolipoprotein (APOE) mRNA is transported to dendrites and may have a role in synaptic structural plasticity. J Neurochem [Epub ahead of print] 2010 April 28. doi:10.1111/j.1471-4159.2010.06773

83.

Orgogozo JM, Gilman S, Dartigues JF et al (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46–54PubMed

84.

Patton RL, Kalback WM, Esh CL et al (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol 169:1048–1063PubMedCrossRef

85.

Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201PubMedCrossRef

86.

Pfeifer M, Boncristiano S, Bondolfi L et al (2002) Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298:1379PubMedCrossRef

87.

Poirier J (2000) Apolipoprotein E and Alzheimer’s disease. A role in amyloid catabolism. Ann N Y Acad Sci 924:81–90PubMedCrossRef

88.

Prada CM, Garcia-Alloza M, Betensky RA et al (2007) Antibody-mediated clearance of amyloid-beta peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging. J Neurosci 27:1973–1980PubMedCrossRef

89.

Pride M, Seubert P, Grundman M et al (2008) Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5:194–196PubMedCrossRef

90.

Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA (2004) Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol 61:1859–1864PubMedCrossRef

91.

Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145PubMedCrossRef

92.

Roher AE, Kuo YM, Esh C et al (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9:112–122PubMed

93.

Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26PubMedCrossRef

94.

Salloway S, Sperling R, Gilman S et al (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–2070PubMedCrossRef

95.

Sato N, Imaizumi K, Manabe T et al (2001) Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem 276:2108–2114PubMedCrossRef

96.

Schellenberg GD, Bird TD, Wijsman EM et al (1992) Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science 258:668–671PubMedCrossRef

97.

Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177PubMedCrossRef

98.

Schenk D, Hagen M, Seubert P (2004) Current progress in beta-amyloid immunotherapy. Curr Opin Immunol 16:599–606PubMedCrossRef

99.

Scolding NJ, Joseph F, Kirby PA et al (2005) Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128:500–515PubMedCrossRef

100.

Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedCrossRef

101.

Serrano-Pozo A, Williams MW, Ferrer I et al (2010) Beneficial effect of human anti-Aβ active immunization on neurite morphology and tau pathology. Brain 133:1312–1327

102.

Shankar GM, Bloodgood BL, 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 27:2866–2875PubMedCrossRef

103.

Sigurdsson EM (2009) Tau-focused immunotherapy for Alzheimer’s disease and related tauopathies. Curr Alzheimer Res 6:446–450PubMedCrossRef

104.

Sigurdsson EM, Knudsen E, Asuni A et al (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer’s disease mouse model immunized with amyloid-beta derivatives. J Neurosci 24:6277–6282PubMedCrossRef

105.

Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159:439–447PubMed

106.

Sleegers K, Brouwers N, Gijselinck I et al (2006) APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983PubMedCrossRef

107.

Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci USA 94:4109–4112PubMedCrossRef

108.

Sorbi S, Nacmias B, Forleo P et al (1993) APP717 and Alzheimer’s disease in Italy. Nat Genet 4:10PubMedCrossRef

109.

St George-Hyslop PH, Tanzi RE, Polinsky RJ et al (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235:885–890PubMedCrossRef

110.

Strittmatter WJ, Saunders AM, 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 USA 90:1977–1981PubMedCrossRef

111.

Sturchler-Pierrat C, Abramowski D, Duke M et al (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292PubMedCrossRef

112.

Sze CI, Troncoso JC, 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 56:933–944PubMedCrossRef

113.

Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRef

114.

Tomic JL, Pensalfini A, Head E, Glabe CG (2009) Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis 35:352–358PubMedCrossRef

115.

Van Broeckhoven C, Backhovens H, Cruts M et al (1992) Mapping of a gene predisposing to early-onset Alzheimer’s disease to chromosome 14q24.3. Nat Genet 2:335–339PubMedCrossRef

116.

van Helmond Z, Boche D, Nicoll J et al (2009) Oligomeric A beta levels following A beta(42) immunisation. Neuropathol Appl Neurobiol 35:25

117.

Veinbergs I, Jung MW, Young SJ et al (1998) Altered long-term potentiation in the hippocampus of apolipoprotein E-deficient mice. Neurosci Lett 249:71–74PubMedCrossRef

118.

Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539PubMedCrossRef

119.

Weller RO (2005) Drainage pathways of CSF and interstitial fluid. In: Kalimo H (ed) Cerebrovascular diseases. ISN Neuropath Press, Basel, pp 50–55

120.

Weller RO, Boche D, Nicoll JA (2009) Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol 118:87–102PubMedCrossRef

121.

Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14PubMedCrossRef

122.

Weller RO, Galea I, Carare RO, Minagar A (2009) Pathophysiology of the lymphatic drainage of the central nervous system: implications for pathogenesis and therapy of multiple sclerosis. Pathophysiology [Epub ahead of print] 2009 Nov 30. doi:10.1016/j.pathophys.2009.10.007

123.

Weninger SC, Yankner BA (2001) Inflammation and Alzheimer disease: the good, the bad, and the ugly. Nat Med 7:527–528PubMedCrossRef

124.

Wharton SB, O’Callaghan JP, Savva GM et al (2009) Population variation in glial fibrillary acidic protein levels in brain ageing: relationship to Alzheimer-type pathology and dementia. Dement Geriatr Cogn Disord 27:465–473PubMedCrossRef

125.

Wilcock DM, Gharkholonarehe N, Van Nostrand WE et al (2009) Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer’s disease. J Neurosci 29:7957–7965PubMedCrossRef

126.

Wilcock DM, Rojiani A, Rosenthal A et al (2004) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflamm 1:24CrossRef

127.

Wisniewski T, Konietzko U (2008) Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol 7:805–811PubMedCrossRef

128.

Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ (1999) Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry 38:11223–11230PubMedCrossRef

129.

Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y (1991) The 717Val–Ile substitution in amyloid precursor protein is associated with familial Alzheimer’s disease regardless of ethnic groups. Biochem Biophys Res Commun 178:1141–1146PubMedCrossRef

130.

Zetterberg H, Mattsson N, Shaw LM, Blennow K (2010) Biochemical markers in Alzheimer’s disease clinical trials. Biomark Med 4:91–98PubMedCrossRef

Title: Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis
Authors: Delphine Boche
Nathan Denham
Clive Holmes
James A. R. Nicoll
Publication date: 01-09-2010
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 3/2010
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0719-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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