TOC1: Characterization of a Selective Oligomeric Tau Antibody

Abstract

The work presented herein addresses a specific portion of the tau pathology, pre-fibrillar oligomers, now thought to be important pathological components in Alzheimer’s disease and other neurodegenerative tauopathies. In previous work, we generated an antibody against purified recombinant cross-linked tau dimers, called Tau Oligomeric Complex 1 (TOC1). TOC1 recognizes tau oligomers and its immunoreactivity is elevated in Alzheimer’s disease brains. In this report, we expand upon the previous study to show that TOC1 selectively labels tau oligomers over monomers or polymers, and that TOC1 is also reactive in other neurodegenerative tauopathies. Using a series of deletion mutants spanning the tau molecule, we further demonstrate that TOC1 has one continuous epitope located within amino acids 209–224, in the so-called proline rich region. Together with the previous study, our data indicates that TOC1 is a conformation-dependent antibody whose epitope is revealed upon dimerization and oligomerization, but concealed again as polymers form. This characterization of the TOC1 antibody further supports its potential as a powerful biochemical tool that can be used to better investigate the involvement of tau in neurodegenerative diseases.

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

“…However, in previous studies we were unable to detect ExoY-induced tau oligomerization in endothelial cell lysates, an effect that was attributed to phosphorylation at Ser 214 , because tau phosphorylation at this site has been shown to inhibit aggregation (57). Recently, Ward et al (68,69) developed TOC1, an antibody that recognizes oligomerized tau with high specificity and sensitivity. In addition, new evidence indicates that hyperphosphorylated, insoluble tau may be released from cells and either accumulate in the extracellular space or be endocytosed by adjacent cells (52).…”

Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

“…Tau oligomer levels have been shown to increase in AD brains prior to NFT formation [18][19][20][21][22][23] and disrupt the ubiquitin proteasome system at synapses [24]. When brain-derived tau oligomers are administered to wild-type (WT) mice, they induce both synaptic and mitochondrial toxicity [25].…”

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…The generation of monoclonal antibodies against different characteristics of Tau pathology has long been based on the extraction of NFT from AD brains and on recombinant Tau purified from Escherichia coli or synthetic peptides (8,10,12). Studies on oligomerization relied on chemically treated recombinant Tau or required preformed aggregates as seeding material (43,44).…”

“…As such, recently developed oligomer-specific antibodies, like T22 (8) or TOC1 (9,10), have been shown to preferentially label neurons at early stages of AD before the formation of NFT. Moreover, these antibodies also improved the discrimination between AD and control patients using total brain extracts, indicating their potential use as a pathophysiological biomarker (8 -10).…”