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The therapeutic effects of intravenous immunoglobulin (IVIG) products were recently studied in Alzheimer's disease (AD) patients. Pilot studies produced encouraging results but phase II and III trials gave disappointing results; a further study is in progress. IVIG products contain antibodies to tau protein, the main component of neurofibrillary tangles (NFTs). The tau used to detect IVIG's anti-tau antibodies in previous studies was non-phosphorylated recombinant human tau-441, but NFT-associated tau is extensively phosphorylated. The objective of this study was to determine if various IVIG products contain specific antibodies to phosphorylated tau (anti-pTau antibodies). ELISAs were used to evaluate binding of six IVIG products to a 12 amino acid peptide, tau 196-207, which was phosphorylated ("pTau peptide") or non-phosphorylated ("non-pTau peptide") at Serine-199 and Serine-202. Both amino acid residues are phosphorylated in AD NFTs. Each IVIG's "anti-pTau antibody ratio" was calculated by dividing its binding to the pTau peptide by its binding to the non-pTau peptide. Seven experiments were performed and data were pooled, with each experiment contributing one data point from each IVIG product. Mean anti-pTau antibody ratios greater than 1.0, suggesting specific antibodies to phosphorylated tau, were found for three IVIG products. Because administration of antibodies to phosphorylated tau has been found to reduce tau-associated pathology in transgenic mouse models of tauopathy, increasing the levels of anti-pTau antibodies, together with other selected antibodies such as anti-Aβ, in IVIG might increase its ability to slow AD's progression., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The effects of intravenous immunoglobulin (IVIG) products are being evaluated in Alzheimer's disease (AD) patients. IVIG contains antibodies to tau protein, the main constituent of neurofibrillary tangles (NFTs). Tau has microtubule binding domain (MBD) repeats which are thought to be necessary for its aggregation, a key process in NFT formation. Tau's N-terminal region may also contribute to its aggregation and to the neurotoxicity of its soluble oligomers. This study examined the specific binding of IVIG products Gammagard, Gamunex, and Flebogamma to a tau N-terminal fragment (tau 45-73), tau's four MBD repeat sequences (tau 244-274, 275-305, 306-336, and 337-368), and a tau C-terminal fragment (tau 422-441). Mean antibody levels to tau 45-73 and tau 422-441 were significantly higher in Gamunex than in Gammagard and Flebogamma, while there were no significant differences between IVIG products for antibody concentrations to the MBD repeat sequences. Patterns of binding to tau fragments differed between IVIG products. Gammagard's highest binding was to tau 275-305 and tau 306-336 while Gamunex bound preferentially to tau 45-73 and tau 422-441. Flebogamma's binding to tau 275-305 and tau 306-336 was greater than to tau 337-368, and its binding to tau 306-336 was also higher than to tau 422-441. These findings indicate that IVIG products vary with respect to their binding to different regions of tau. This could result in differences with regard to their ability to prevent tau's aggregation and/or tau soluble oligomer neurotoxicity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Intravenous immunoglobulin (IVIG) products are prepared from plasma immunoglobulins from healthy donors. Pilot studies suggest that IVIG may stabilize cognitive functioning in patients with mild-to-moderate Alzheimer's disease. This study measured antibodies to recombinant human tau protein in the IVIG products Gammagard (Baxter), Gamunex (Talecris), and Flebogamma (Grifols). Anti-tau antibodies were measured by ELISA, subtracting IVIG's polyvalent binding from its binding to tau-coated wells to calculate specific anti-tau antibody levels. Because polyvalent binding of IVIG products may interfere with ELISA measurement of their specific antibody levels, the percentage of binding of each IVIG product to tau-coated wells that was specific for tau was also determined. Specific anti-tau antibodies were detected in all three IVIG products, with significant differences between these products (p<0.001) even when Flebogamma's anti-tau antibodies were doubled to account for its preparation as a 5% solution vs. 10% solutions for Gammagard and Gamunex (means: Gammagard, 3.1 μg/ml; Gamunex, 2.5 μg/ml; Flebogamma, 1.2 μg/ml). The percentages of each IVIG product's specific binding to tau-coated wells also varied between the various products (p<0.001) and between all pairs of IVIG products (means: Gammagard, 73.1%; Flebogamma, 54.5%; Gamunex, 37.4%; p<0.01 for all pairwise comparisons). These findings indicate that IVIG products contain specific anti-tau antibodies. The concentrations of these antibodies and the percentages of specific binding of IVIG to tau-coated wells vary between IVIG products. Further studies are indicated to determine if IVIG also contains antibodies to pathologic forms of tau., (Copyright © 2013 Elsevier B.V. All rights reserved.)

α-Synuclein is thought to contribute to the pathogenesis of Parkinson's disease (PD). It is the main protein in Lewy bodies, the pathognomonic inclusion bodies in the PD substantia nigra, and mutations which increase its aggregation and/or expression are associated with familial early-onset parkinsonism. Soluble oligomers are considered to be α-synuclein's most neurotoxic conformation. We previously reported that intravenous immunoglobulin (IVIG) products contain specific antibodies to α-synuclein which do not prevent development of four-day α-synuclein oligomers. The objective of this study was to further examine IVIG's effects on α-synuclein's aggregation and neurotoxicity. The IVIG product Gammagard (Baxter Healthcare) did not prevent the development of nine-day α-synuclein oligomers, nor did it degrade preformed oligomers, as shown by western blots performed on gels run under reducing/denaturing conditions and native gels. In western blots of native gels, an additional low molecular weight band (~22 kDa) was detected in α-synuclein incubated for four days in Gammagard, but not in Gammagard alone. No significant differences were found for Thioflavin-T reactivity between α-synuclein amorphous aggregates grown in Gammagard vs. those grown in phosphate-buffered saline. Gammagard partially protected SK-N-BE(2)M17 human neuroblastoma cells against α-synuclein oligomer toxicity (p = 0.007 vs. protective effects of normal human IgG). These findings suggest that although IVIG does not prevent α-synuclein aggregation, it still may reduce α-synuclein neurotoxicity through an unknown mechanism., (Copyright © 2012 Elsevier B.V. All rights reserved.)