Skip to main content
PMC home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2008 Jul;5(3):415–420. doi: 10.1016/j.nurt.2008.05.013

Targeting β-amyloid pathology in Alzheimer’s disease with Aβ immunotherapy

Roger M Nitsch 1,✉, Christoph Hock 1
PMCID: PMC5084243  PMID: 18625453

Summary

More than 10 clinical trials of Aβ immunotherapy are currently underway in patients with Alzheimer’s disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain β-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid β-peptide (Aβ). Initial experimental and neuro-pathological evidence for clearance of brain β-amyloid in response to Aβ immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of Aβ immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted cross-reactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with pre-existing vascular amyloid pathology, possible relocalization of Aβ from β-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of Aβ antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of Aβ to be therapeutic ally targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble Aβ into toxic oligomeric aggregation intermediates in the dynamic equilibrium of β-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for Aβ immunotherapy to be one of the first disease-modifying therapies of Alzheimer’s disease to be introduced into clinical practice.

Key Words: Humanized monoclonal antibody, neurodegeneration, vaccination, clinical trial, APP, passive immunization

References

  • 1.Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–177. doi: 10.1038/22124. [DOI] [PubMed] [Google Scholar]
  • 2.Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408:979–982. doi: 10.1038/35050110. [DOI] [PubMed] [Google Scholar]
  • 3.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;48:567–579. doi: 10.1002/1531-8249(200010)48:4<567::AID-ANA3>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  • 4.Lemere CA, Maron R, Selkoe DJ, Weiner HL. Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer’s disease. DNA Cell Biol. 2001;20:705–711. doi: 10.1089/10445490152717569. [DOI] [PubMed] [Google Scholar]
  • 5.Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol. 2001;159:439–447. doi: 10.1016/S0002-9440(10)61715-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lemere CA, Beierschmitt A, Iglesias M, et al. Alzheimer’s disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol. 2004;165:283–297. doi: 10.1016/S0002-9440(10)63296-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol. 2006;6:404–416. doi: 10.1038/nri1843. [DOI] [PubMed] [Google Scholar]
  • 8.Schenk D, Hagen M, Seubert P. Current progress in beta-amyloid immunotherapy. Curr Opin Immunol. 2004;16:599–606. doi: 10.1016/j.coi.2004.07.012. [DOI] [PubMed] [Google Scholar]
  • 9.Solomon B. Antibody-mediated immunotherapy for Alzheimer’s disease. Curr Opin Investig Drugs. 2007;8:519–524. [PubMed] [Google Scholar]
  • 10.Brody DL, Holtzman DM. Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci 2008 Mar 19; [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  • 11.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 disease. Nat Med. 2000;6:916–919. doi: 10.1038/78682. [DOI] [PubMed] [Google Scholar]
  • 12.Bacskai BJ, Kajdasz ST, Christie RH, et al. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med. 2001;7:369–372. doi: 10.1038/85525. [DOI] [PubMed] [Google Scholar]
  • 13.DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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;98:8850–8855. doi: 10.1073/pnas.151261398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Bacskai BJ, Kajdasz ST, McLellan ME, et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002;22:7873–7878. doi: 10.1523/JNEUROSCI.22-18-07873.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/-knock-out mice. J Neurosci. 2003;23:8532–8538. doi: 10.1523/JNEUROSCI.23-24-08532.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Wilcock DM, Rojiani A, Rosenthal A, et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci. 2004;24:6144–6151. doi: 10.1523/JNEUROSCI.1090-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Wilcock DM, Rojiani A, Rosenthal A, et al. 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 Neuroinflammation. 2004;1:24–24. doi: 10.1186/1742-2094-1-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Boyett KW, DiCarlo G, Jantzen PT, et al. Increased fibrillar beta-amyloid in response to human clq injections into hippocampus and cortex of APP+PS1 transgenic mice. Neurochem Res. 2003;28:83–93. doi: 10.1023/A:1021600212829. [DOI] [PubMed] [Google Scholar]
  • 19.Wilcock DM, Jantzen PT, Li Q, Morgan D, Gordon MN. Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. Neuroscience. 2007;144:950–960. doi: 10.1016/j.neuroscience.2006.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Lombardo JA, Stem EA, McLellan ME, et al. Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci. 2003;23:10879–10883. doi: 10.1523/JNEUROSCI.23-34-10879.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004;43:321–332. doi: 10.1016/j.neuron.2004.07.003. [DOI] [PubMed] [Google Scholar]
  • 22.Klyubin I, Walsh DM, Lemere CA, et al. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med. 2005;11:556–561. doi: 10.1038/nm1234. [DOI] [PubMed] [Google Scholar]
  • 23.Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM. Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci. 2007;27:7648–7653. doi: 10.1523/JNEUROSCI.0395-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Bales KR, Tzavara ET, Wu S, et al. Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. J Clin Invest. 2006;116:825–832. doi: 10.1172/JCI27120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Mohajeri MH, Saini K, Schultz JG, Wollmer MA, Hock C, Nitsch RM. Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer’s disease-causing mutation. J Biol Chem. 2002;277:33012–33017. doi: 10.1074/jbc.M203193200. [DOI] [PubMed] [Google Scholar]
  • 26.Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408:982–985. doi: 10.1038/35050116. [DOI] [PubMed] [Google Scholar]
  • 27.Sigurdsson EM, Knudsen E, Asuni A, et al. An attenuated immune response is sufficient to enhance cognition in an Alzheimer’s disease mouse model immunized with amyloid-beta derivatives. J Neurosci. 2004;24:6277–6282. doi: 10.1523/JNEUROSCI.1344-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chen G, Chen KS, Kobayashi D, et al. Active beta-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of beta-amyloid. J Neurosci. 2007;27:2654–2662. doi: 10.1523/JNEUROSCI.3710-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Pfeifer M, Boncristiano S, Bondolfi L, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002;298:1379–1379. doi: 10.1126/science.1078259. [DOI] [PubMed] [Google Scholar]
  • 30.Racke MM, Boone LI, Hepburn DL, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25:629–636. doi: 10.1523/JNEUROSCI.4337-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Taguchi H, Planque S, Nishiyama Y, et al. Autoantibody-catalyzed hydrolysis of amyloid beta peptide. J Biol Chem. 2008;283:4714–4722. doi: 10.1074/jbc.M707983200. [DOI] [PubMed] [Google Scholar]
  • 32.Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64:94–101. doi: 10.1212/01.WNL.0000148604.77591.67. [DOI] [PubMed] [Google Scholar]
  • 33.Ride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis. 2008;5:194–196. doi: 10.1159/000113700. [DOI] [PubMed] [Google Scholar]
  • 34.Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–452. doi: 10.1038/nm840. [DOI] [PubMed] [Google Scholar]
  • 35.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. doi: 10.1212/01.wnl.0000073623.84147.a8. [DOI] [PubMed] [Google Scholar]
  • 36.Hock C, Konietzko U, Papassotiropoulos A, et al. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 2002;8:1270–1275. doi: 10.1038/nm783. [DOI] [PubMed] [Google Scholar]
  • 37.Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–1562. doi: 10.1212/01.WNL.0000159740.16984.3C. [DOI] [PubMed] [Google Scholar]
  • 38.Hock C, Konietzko U, Streffer JR, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron. 2003;38:547–554. doi: 10.1016/S0896-6273(03)00294-0. [DOI] [PubMed] [Google Scholar]
  • 39.Black RS SR, Kirby L, Safirstein B, Motter R, Pallay A. A single ascending dose study of bapineuzumab, a humanized monoclonal antibody to Aβ, in AD. Paper presented at: 9th International Symposium on Alzheimer Therapy; July 19, 2006; Geneva, Switzerland.
  • 40.Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials. Arch Neurol. 2007;64:1323–1329. doi: 10.1001/archneur.64.9.1323. [DOI] [PubMed] [Google Scholar]
  • 41.Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol. 2004;14:11–20. doi: 10.1111/j.1750-3639.2004.tb00493.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Masliah E, Hansen L, Adame A, et al. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology. 2005;64:129–131. doi: 10.1212/01.WNL.0000148590.39911.DF. [DOI] [PubMed] [Google Scholar]
  • 43.Bombois S, Maurage CA, Gompel M, et al. Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol. 2007;64:583–587. doi: 10.1001/archneur.64.4.583. [DOI] [PubMed] [Google Scholar]
  • 44.Patton RL, Kalback WM, Esh CL, et al. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol. 2006;169:1048–1063. doi: 10.2353/ajpath.2006.060269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Wilcock DM, Alamed J, Gottschall PE, et al. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci. 2006;26:5340–5346. doi: 10.1523/JNEUROSCI.0695-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Relkin NR. Beyond symptomatic therapy: a re-examination of acetylcholinesterase inhibitors in Alzheimer’s disease. Expert Rev Neurother. 2007;7:735–748. doi: 10.1586/14737175.7.6.735. [DOI] [PubMed] [Google Scholar]
  • 47.Prada CM, Garcia-Alloza M, Betensky RA, et al. Antibody-mediated clearance of amyloid-beta peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging. J Neurosci. 2007;27:1973–1980. doi: 10.1523/JNEUROSCI.5426-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Fox NC, Black RS, Gilman S, et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005;64:1563–1572. doi: 10.1212/01.WNL.0000159743.08996.99. [DOI] [PubMed] [Google Scholar]
  • 49.Nicoll JA, Barton E, Boche D, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006;65:1040–1048. doi: 10.1097/01.jnen.0000240466.10758.ce. [DOI] [PubMed] [Google Scholar]
  • 50.Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293:1491–1495. doi: 10.1126/science.1062097. [DOI] [PubMed] [Google Scholar]
  • 51.Ferrari A, Hoerndli F, Baechi T, Nitsch RM, Gotz J. beta-Amyloid induces paired helical filament-like tau filaments in tissue culture. J Biol Chem. 2003;278:40162–40168. doi: 10.1074/jbc.M308243200. [DOI] [PubMed] [Google Scholar]
  • 52.King ME, Kan HM, Baas PW, Erisir A, Glabe CG, Bloom GS. Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol. 2006;175:541–546. doi: 10.1083/jcb.200605187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293:1487–1491. doi: 10.1126/science.1058189. [DOI] [PubMed] [Google Scholar]
  • 54.Oddo S, Caccamo A, Tran L, et al. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem. 2006;281:1599–1604. doi: 10.1074/jbc.M507892200. [DOI] [PubMed] [Google Scholar]
  • 55.Lesne S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–357. doi: 10.1038/nature04533. [DOI] [PubMed] [Google Scholar]
  • 56.Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 2008. [DOI] [PMC free article] [PubMed]
  • 57.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;416:535–539. doi: 10.1038/416535a. [DOI] [PubMed] [Google Scholar]
  • 58.Walsh DM, Selkoe DJ. A beta oligomers — a decade of discovery. J Neurochem. 2007;101:1172–1184. doi: 10.1111/j.1471-4159.2006.04426.x. [DOI] [PubMed] [Google Scholar]
  • 59.Knobloch M, Konietzko U, Krebs DC, Nitsch RM. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging. 2007;28:1297–1306. doi: 10.1016/j.neurobiolaging.2006.06.019. [DOI] [PubMed] [Google Scholar]
  • 60.Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT. Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004;24:4535–4540. doi: 10.1523/JNEUROSCI.0462-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–319. doi: 10.1002/ana.20009. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES