ELISA measurement of specific antibodies to phosphorylated tau in intravenous immunoglobulin products

Loeffler, David A.; Klaver, Andrea C.; Coffey, Mary P.

doi:10.1016/j.intimp.2015.08.022

Cited by 7 publications

(13 citation statements)

References 19 publications

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“…IVIG can inhibit complement activation, neutralize inflammatory cytokines, and modulate chemokine expression and regulatory T cell subsets. IVIG has been used to treat a range of autoimmune, infectious and idiopathic disorders, but it is not approved for Alzheimer’s disease and negative results were reported in a phase III IVIG study [ 57 ]. Those disappointing results have reduced people’s enthusiasm for developing IVIG as a possible treatment for AD; however, it is still too early to draw final conclusions [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

“…IVIG has been used to treat a range of autoimmune, infectious and idiopathic disorders, but it is not approved for Alzheimer’s disease and negative results were reported in a phase III IVIG study [ 57 ]. Those disappointing results have reduced people’s enthusiasm for developing IVIG as a possible treatment for AD; however, it is still too early to draw final conclusions [ 57 ]. Several suggestions have been proposed for IVIG, such as earlier IVIG treatment, increasing concentration and anti-inflammatory activity, generation of IVIG products with recombinant technology, using the IVIG polyclonal antibody approach, etc .…”

Section: Discussionmentioning

confidence: 99%

“…Several suggestions have been proposed for IVIG, such as earlier IVIG treatment, increasing concentration and anti-inflammatory activity, generation of IVIG products with recombinant technology, using the IVIG polyclonal antibody approach, etc . All of those were in an effort to deplete aggregated Aβ species [ 57 ]. Here, our results suggested that oxidatively-modified immunoglobulins and the resulting alteration in biological properties may be another reason for the failures of IVIG trials.…”

Section: Discussionmentioning

confidence: 99%

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Redox Proteomic Profiling of Specifically Carbonylated Proteins in the Serum of Triple Transgenic Alzheimer’s Disease Mice

Shen

Chen

Yang

et al. 2016

IJMS

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Oxidative stress is a key event in the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD). To investigate the role of oxidative stress in AD and to search for potential biomarkers in peripheral blood, serums were collected in this study from the 3-, 6-, and 12-month-old triple transgenic AD mice (3×Tg-AD mice) and the age- and sex-matched non-transgenic (non-Tg) littermates. The serum oxidized proteins were quantified by slot-blot analysis and enzyme-linked immunosorbent assay (ELISA) to investigate the total levels of serum protein carbonyl groups. Western blotting, in conjunction with two-dimensional gel electrophoresis (2D-Oxyblot), was employed to identify and quantify the specifically-carbonylated proteins in the serum of 3×Tg-AD mice. The results showed that the levels of serum protein carbonyls were increased in the three month old 3×Tg-AD mice compared with the non-Tg control mice, whereas no significant differences were observed in the six and 12 months old AD mice, suggesting that oxidative stress is an early event in AD progression. With the application of 2D-Oxyblot analysis, (immunoglobin) Ig gamma-2B chain C region (IGH-3), Ig lambda-2 chain C region (IGLC2), Ig kappa chain C region (IGKC), and Ig kappa chain V-V region HP R16.7 were identified as significantly oxidized proteins compared with the control. Among them IGH-3 and IGKC were validated via immunoprecipitation and Western blot analysis. Identification of oxidized proteins in the serums of 3×Tg-AD mice can not only reveal potential roles of those proteins in the pathogenesis of AD but also provide potential biomarkers of AD at the early stage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Redox Proteomic Profiling of Specifically Carbonylated Proteins in the Serum of Triple Transgenic Alzheimer’s Disease Mice

Shen

Chen

Yang

et al. 2016

IJMS

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“…Using an ELISA which controlled for polyvalent binding, we detected specific antibodies (IgG) to non-phosphorylated tau (recombinant human tau-441, 2N4R) in three intravenous immunoglobulin (IVIG) products [ 35 ]. However, in a later study using an ELISA which also controlled for binding to non-phosphorylated epitopes on phosphorylated tau, we found specific antibodies to a phosphorylated tau peptide in only three of six IVIG preparations [ 37 ]. This result raised questions about the presence of specific anti-phospho-tau antibodies in healthy individuals, leading to the present investigation.…”

Section: Introductionmentioning

confidence: 99%

“…This result raised questions about the presence of specific anti-phospho-tau antibodies in healthy individuals, leading to the present investigation. This was an exploratory study whose primary goal was to determine the frequency of specific serum IgG and IgM binding to a phosphorylated and non-phosphorylated tau peptide (the same tau peptide that was used in our earlier IVIG study [ 37 ]) in individuals with NCI, MCI, or AD. The secondary goal in this study was to compare the specific anti-tau antibody levels between these diagnostic groups.…”

Section: Introductionmentioning

confidence: 99%

Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired, mildly cognitively impaired, and Alzheimer’s disease subjects: an exploratory study

Klaver

Coffey

Bennett

et al. 2017

Transl Neurodegener

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BackgroundTau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy, suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer’s disease (AD). The extent to which individuals with no cognitive impairment (NCI) possess serum anti-tau antibodies, and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment (MCI) or AD, are unclear. Previous studies measuring these antibodies did not account for antibody polyvalent binding, which can be extensive, nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those peptides.MethodsAn ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated (“pTau;” phosphorylated at Serine-199 and Serine-202) and non-phosphorylated (“non-pTau”) tau 196-207 in subjects with NCI, MCI, or AD (n = 10/group). Between-group differences in these antibody levels were evaluated for statistical significance, and correlations were examined in pooled data from all subjects between these antibody levels and subject age, global cognitive functioning, and NFT counts.ResultsSpecific IgG binding to pTau and non-pTau was detected in all subjects except for one NCI control. Specific IgM binding was detected to pTau in all subjects except for two AD patients, and to non-pTau in all subjects. Mean pTau IgG was increased in MCI subjects by 53% and 70% vs. AD and NCI subjects respectively (both p < 0.05), while no significant differences were found between groups for non-pTau IgG (p = 0.052), pTau IgM, or non-pTau IgM. Non-pTau IgG was negatively associated with global cognition (Spearman rho = −0.50).ConclusionsSpecific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive status. Serum IgG to phosphorylated tau may be increased in individuals with MCI, but this unexpected finding requires confirmation. The approach used in this study to measure specific serum antibodies to phosphorylated tau should be useful for measuring antibodies to other post-translationally-modified proteins that are of relevance to neurodegenerative disorders.

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Characterization of isolated tau-reactive antibodies from the IVIG product, plasma of patients with Alzheimer's disease and cognitively normal individuals

Krestova

Hromádková

Bı́lková

et al. 2017

Journal of Neuroimmunology

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ELISA measurement of specific antibodies to phosphorylated tau in intravenous immunoglobulin products

Cited by 7 publications

References 19 publications

Redox Proteomic Profiling of Specifically Carbonylated Proteins in the Serum of Triple Transgenic Alzheimer’s Disease Mice

Redox Proteomic Profiling of Specifically Carbonylated Proteins in the Serum of Triple Transgenic Alzheimer’s Disease Mice

Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired, mildly cognitively impaired, and Alzheimer’s disease subjects: an exploratory study

Characterization of isolated tau-reactive antibodies from the IVIG product, plasma of patients with Alzheimer's disease and cognitively normal individuals

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