Effect of Different Aβ Aggregates as Antigen on the Measure of Naturally Occurring Autoantibodies against Amyloid-β40/42 in IVIG

Author(s): Haijun Cao, Xi Du, Renyong Zeng, Zhaoji Lv, Shengliang Ye, Peng Jiang, Zongkui Wang, Li Ma, Yun Huang*, Changqing Li*, Rong Zhang, Fengjuan Liu

Journal Name: Current Alzheimer Research

Volume 16 , Issue 14 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: The specific Intravenous Immunoglobulin (IVIG) for Alzheimer’s Disease (AD) is developing, which contains a high level of naturally occurring autoantibodies against amyloid-β (nAbs-Aβ), and the measure of nAbs-Aβ content is greatly essential. Though Enzyme-Linked Immunosorbent Assay (ELISA) has been widely used in detecting the nAbs-Aβ content, the impact of Aβ aggregates species chosen as antigen in ELISA on this measure has not been evaluated.

Objective: To clarify the influence of different Aβ40/42 aggregates as antigen during ELISA on the content of nAbs-Aβ40/42 measured in IVIG.

Method: Preparation of various Aβ40/42 aggregates was performed by different aggregation solutions and various lengths of time, and analyzed by western blot. Different Aβ40/42 aggregates as antigen were adopted to measure the nAbs-Aβ40/42 content in IVIG by ELISA, and the control was carried out to reduce interference of nonspecific binding. The Bonferroni and Dunnett’s T3 were used for statistical analysis.

Results: The duration for the formation of Aβ40/42 aggregates had more effect on detecting nAbs-Aβ40/42 content in IVIG than the aggregation solution. Higher content of nAbs-Aβ40/42 in the same IVIG was displayed when measured with Aβ40/42 aggregates at day 3, instead of at day 0.5 and day 7.0. The nAbs- Aβ40/42 contents in the same IVIG measured with Aβ40/42 aggregates prepared in different solutions were obviously different, but there was no significant regularity among them.

Conclusion: The nAbs-Aβ40/42 content in the same IVIG is significantly different when measured with Aβ40/42 aggregated under different conditions. The nAbs-Aβ40/42 content in IVIG by antigen-dependent measures, like ELISA, is uncertain.

Keywords: Naturally occurring autoantibodies against amyloid-β, intravenous immunoglobulin, Alzheimer's disease, measure, amyloid β-protein, aggregate.

Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline. 2017. Alzheimers Dement (N Y) 3(3): 367-84. (2017)
[http://dx.doi.org/10.1016/j.trci.2017.05.002] [PMID: 29067343]
2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14: 367-429. (2018)
Ma TJ, Gao J, Liu Y, Zhuang JH, Yin C, Li P, et al. nanomedicine strategies for sustained, controlled and targeted treatment of Alzheimer’s disease. Mini Rev Med Chem 18(12): 1035-46. (2018)
[http://dx.doi.org/10.2174/1389557518666171215150024] [PMID: 29243575]
Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement 4: 195-214. (2018)
[http://dx.doi.org/10.1016/j.trci.2018.03.009] [PMID: 29955663]
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3(3): 186-91. (2007)
[http://dx.doi.org/10.1016/j.jalz.2007.04.381] [PMID: 19595937]
Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, et al. Intravenous immunoglobulins as a treatment for Alzheimer’s disease: rationale and current evidence. Drugs 70(5): 513-28. (2010)
[http://dx.doi.org/10.2165/11533070-000000000-00000] [PMID: 20329802]
Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol 139(3S): S1-S46. (2017)
[http://dx.doi.org/10.1016/j.jaci.2016.09.023] [PMID: 28041678]
Relkin NR, Thomas RG, Rissman RA. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 88(18): 1768-75. (2017)
[http://dx.doi.org/10.1212/WNL.0000000000003904] [PMID: 28381506]
Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol 34(1): S74-9. (2014)
[http://dx.doi.org/10.1007/s10875-014-0041-4] [PMID: 24760112]
Counts SE, Lahiri DK. Overview of immunotherapy in Alzheimer’s disease (AD) and mechanisms of IVIG neuroprotection in preclinical models of AD. Curr Alzheimer Res 11(7): 623-5. (2014)
[http://dx.doi.org/10.2174/156720501107140815102453] [PMID: 25156573]
Loeffler DA. Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered? J Neuroinflammation 11: 198. (2014)
[http://dx.doi.org/10.1186/s12974-014-0198-z] [PMID: 25476011]
Lardenoije R, van den Hove DLA, Jung SE, Havermans M, Blackburn P, Liu B, et al. Active amyloid-β vaccination results in epigenetic changes in the hippocampus of an Alzheimer’s disease-like mouse model. Curr Alzheimer Res 16(9): 861-70. (2019)
[http://dx.doi.org/10.2174/1567205016666190827122009] [PMID: 31453788]
Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T, et al. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease. J Neuroinflammation 7: 90. (2010)
[http://dx.doi.org/10.1186/1742-2094-7-90] [PMID: 21138577]
Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25(36): 8240-9. (2005)
[http://dx.doi.org/10.1523/JNEUROSCI.1808-05.2005] [PMID: 16148231]
Puli L, Pomeshchik Y, Olas K, Malm T, Koistinaho J, Tanila H. Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflammation 9: 105. (2012)
[http://dx.doi.org/10.1186/1742-2094-9-105] [PMID: 22642812]
Onodera H, Nakagawa R, Nakagawa H, Urayama T, Haino K, Yunoki M. Long-term monitoring of virus antibody titers in human intravenous immunoglobulin lots derived from donors in Japan. Transfusion 58(11): 2617-26. (2018)
[http://dx.doi.org/10.1111/trf.14908] [PMID: 30284288]
Ye S, Lei M, Jiang P, Liu F, Wang Z, Cao H, et al. Demonstration of the IgG antibody repertoire against the bacteria Escherichia coli in Chinese intravenous immunoglobulins. J Pharm Biomed Anal 133: 8-14. (2017)
[http://dx.doi.org/10.1016/j.jpba.2016.10.018] [PMID: 27792896]
Lahiri DK, Ray B. Intravenous immunoglobulin treatment preserves and protects primary rat hippocampal neurons and primary human brain cultures against oxidative insults. Curr Alzheimer Res 11(7): 645-54. (2014)
[http://dx.doi.org/10.2174/1567205011666140812113851] [PMID: 25115544]
Counts SE, Ray B, Mufson EJ, Perez SE, He B, Lahiri DK. Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer’s disease. J Clin Immunol 34(1): S80-5. (2014)
[http://dx.doi.org/10.1007/s10875-014-0020-9] [PMID: 24760109]
Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, et al. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 52(2): 253-6. (2002)
[http://dx.doi.org/10.1002/ana.10253] [PMID: 12210803]
Wang T, Xie XX, Ji M, Wang SW, Zha J, Zhou WW, et al. Naturally occurring autoantibodies against Aβ oligomers exhibited more beneficial effects in the treatment of mouse model of Alzheimer’s disease than intravenous immunoglobulin. Neuropharmacology 105: 561-76. (2016)
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.015] [PMID: 26907803]
Ye S, Zeng R, Jiang P, Hou M, Liu F, Wang Z, et al. Concentrations of antibodies against β-amyloid 40/42 monomer and oligomers in Chinese intravenous immunoglobulins. J Pharm Biomed Anal 138: 277-82. (2017)
[http://dx.doi.org/10.1016/j.jpba.2017.02.024] [PMID: 28231531]
Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, et al. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem 95(3): 834-47. (2005)
[http://dx.doi.org/10.1111/j.1471-4159.2005.03407.x] [PMID: 16135089]
Ryan DA, Narrow WC, Federoff HJ, Bowers WJ. An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. J Neurosci Methods 190(2): 171-9. (2010)
[http://dx.doi.org/10.1016/j.jneumeth.2010.05.001] [PMID: 20452375]
Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75(10): 1472-4. (2004)
[http://dx.doi.org/10.1136/jnnp.2003.033399] [PMID: 15377700]
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, et al. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 30(11): 1728-36. (2009)
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.12.021] [PMID: 18294736]
Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 12(3): 233-43. (2013)
[http://dx.doi.org/10.1016/S1474-4422(13)70014-0] [PMID: 23375965]
Kile S, Au W, Parise C. IVIG treatment of mild cognitive impairment due to Alzheimer’s disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry 88(2): 106-12. (2017)
[http://dx.doi.org/10.1136/jnnp-2015-311486] [PMID: 26420886]
Moreth J, Mavoungou C, Schindowski K. Passive anti-amyloid immunotherapy in Alzheimer’s disease: what are the most promising targets? Immun Ageing 10(1): 18. (2013)
[http://dx.doi.org/10.1186/1742-4933-10-18] [PMID: 23663286]
Knight EM, Gandy S. Immunomodulation and AD-down but not out. J Clin Immunol 34(1): S70-3. (2014)
[http://dx.doi.org/10.1007/s10875-014-0039-y] [PMID: 24781637]
Relkin NR, Mujalli DM, Shenoy SA, Adamiak B, Weksler ME, Kayed R, et al. IVIG contains antibodies against oligomers and fibrils of beta amyloid. Alzheimers Dement 3: S196. (2007)
Klaver AC, Patrias LM, Coffey MP, Finke JM, Loeffler DA. Measurement of anti-Abeta1-42 antibodies in intravenous immunoglobulin with indirect ELISA: the problem of nonspecific binding. J Neurosci Methods 187(2): 263-9. (2010)
[http://dx.doi.org/10.1016/j.jneumeth.2010.01.018] [PMID: 20097229]
Balakrishnan K, Andrei-Selmer LC, Selmer T, Bacher M, Dodel R. Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against amyloid-beta. J Alzheimers Dis 20(1): 135-43. (2010)
[http://dx.doi.org/10.3233/JAD-2010-1353] [PMID: 20164596]
Klaver AC, Finke JM, Digambaranath J, Balasubramaniam M, Loeffler DA. Antibody concentrations to Abeta1-42 monomer and soluble oligomers in untreated and antibody-antigen-dissociated intravenous immunoglobulin preparations. Int Immunopharmacol 10(1): 115-9. (2010)
[http://dx.doi.org/10.1016/j.intimp.2009.10.005] [PMID: 19840873]
Klaver AC, Coffey MP, Smith LM, Loeffler DA. Comparison of ELISA measurements of anti-Aβ concentrations and percentages of specific binding to Aβ between unfractionated intravenous immunoglobulin products and their purified anti-Aβ antibodies. Immunol Lett 154(1-2): 7-11. (2013)
[http://dx.doi.org/10.1016/j.imlet.2013.07.008] [PMID: 23928186 ]
Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3): 349-57. (2012)
[http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176]
Stine WB Jr, Dahlgren KN, Krafft GA, LaDu MJ. In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem 278(13): 11612-22. (2003)
[http://dx.doi.org/10.1074/jbc.M210207200] [PMID: 12499373 ]
Sokolow S, Henkins KM, Bilousova T, Miller CA, Vinters HV, Poon W, et al. AD synapses contain abundant Aβ monomer and multiple soluble oligomers, including a 56-kDa assembly. Neurobiol Aging 33(8): 1545-55. (2012)
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.05.011] [PMID: 21741125]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 28 January, 2020
Page: [1290 - 1299]
Pages: 10
DOI: 10.2174/1567205017666200102151731
Price: $65

Article Metrics

PDF: 23