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

• Tau protein is extensively phosphorylated in neurofibrillary tangles.
• Therapeutic effects of IVIG have recently been explored in Alzheimer's.
• We detected specific antibodies to phosphorylated tau in 3 of 6 IVIG products.
• Increasing these antibodies might increase IVIG's chances to slow AD's progression.

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.

IVIG binding was measured to phosphorylated and non-phosphorylated tau 196–207. An anti-pTau antibody ratio > 1, indicative of the presence of specific anti-phospho-tau antibodies, was detected in three IVIG preparations.Figure optionsDownload as PowerPoint slide