TOC1: A valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy

Abstract

All tauopathies result in various forms of cognitive decline and neuronal loss. Although in some diseases, tau mutations appear to cause neurodegeneration, the toxic “form” of tau remains elusive. Tau is the major protein found within neurofibrillary tangles (NFTs) and therefore it seemed rational to assume that aggregation of tau monomers into NFTs was causal to the disease process. However, the appearance of oligomers rather than NFTs coincides much better with the voluminous neuronal loss in many of these diseases. In this study, we utilized the bigenic mouse line (rTg4510) which conditionally expresses P301L human tau. A novel tau antibody, termed Tau Oligomer Complex 1 (TOC1) was employed to probe mouse brains and assess disease progression. TOC1 selectively recognizes dimers/oligomers and appears to constitute an early stage marker of tau pathology. Its peak reactivity is coincident with other well-known early stage pathological markers such as MC1 and the early-stage phospho-marker CP13. TOC1’s reactivity depends on the conformation of the tau species since it does not react with monomer under native conditions, although it does react with monomers under SDS-denaturation. This indicates a conformational change must occur within the tau aggregate to expose its epitope. Tau oligomers preferentially form under oxidizing conditions and within this mouse model, we observe tau oligomers forming at an increased rate and persisting much longer, most likely due to the aggressive P301L mutation. With the help of other novel antibodies, the use of this antibody will aid in providing a better understanding of tau toxicity within Alzheimer’s disease and other tauopathies.

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).…”

“…There is no consistent standard for the molecular mass of tau oligomers; in fact, reports of tau oligomer molecular weights vary greatly, even in studies utilizing the TOC1 antibody (69). Such variability has largely been attributed to the tau isoform expressed in the cell or organ evaluated (13), the degree and site(s) of posttranslational modification, including phosphorylation (27), and the susceptibility of the tau oligomer to proteolytic cleavage (20) (see Ref.…”

Azaphilones Inhibit Tau Aggregation and Dissolve Tau Aggregates in Vitro

“…Solutions were passed through a nitrocellulose membrane using house vacuum in a dot-blot apparatus. The aggregates trapped on the membrane were detected by either general antibodies (a mixture of Tau 5 39 at 1:50,000 dilution, Tau 12 40 at 1:250,000 dilution and Tau 7 41 at 1:250,000 dilution), or antibodies to toxic conformations (TNT1 19 at 1:200,000 or TOC1 20 at 1:7,000). All antibodies were a kind gift from Drs.…”

Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy

“…The TNT1 antibody is a marker that indicates whether PAD is exposed in tau, and the pattern of TNT1 staining in neurons suggests PAD exposure is a very early pretangle pathological change in tau in AD (23, 24). Second, a recently characterized antibody called tau-oligomer complex 1 (TOC1) selectively labels tau oligomers over monomeric or filamentous tau (25, 26, 28–30). A number of disease-relevant modifications of tau, including oligomer formation, appear to alter tau conformation in ways that aberrantly expose PAD (29, 31).…”