PubMed: 22817713

Tau oligomers and tau toxicity in neurodegenerative disease.
Biochemical Society transactions
Binder LI | Himmelstein DS | Lancia JK | Ward SM

Evidence a7b40274fe

Employing recombinant full-length hT40, we observe the presence of oligomers approximately 15 min after the addition of the anionic inducer arachidonic acid, whereas filament formation requires 5–6 h to attain steady state (Figures 1A–1C)

Evidence 1a858548e9

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2]

Evidence 8b77f2a043

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau

Evidence cb1644afff

Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect

Evidence 298ed2888f

We discovered that aggregated tau inhibits FAT only in the anterograde direction at physiological tau levels, whereas tau monomers had no effect on FAT in either direction, even at concentrations of tau >10-fold higher than

Evidence a0fc9379b4

However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21]

Evidence 7de7530d8a

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology

Evidence 3886577992

Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease

Evidence 07dc5753ca

This indicates that tau oligomers represent the main toxic species responsible for neurodegeneration associated with AD

Evidence 28d96f17ba

Time-course aggregation analysis revealed that dimerization precedes tau oligomerization which, in turn, is an earlier event than the formation of full-length filaments

Evidence f990a9e5a6

TOC1’s immunoreactivity is greatly elevated in AD brains compared with healthy controls, but co-localizes best with early-stage markers for AD pathogenesis such as pS422 [16]

Evidence 8e56771422

Tau’s primary role within neurons is thought to be the regulation and stabilization of microtubule dynamics [1,2]

Evidence 227f470f5d

We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau

Evidence e3e12f53f8

However, our data indicate that Hsp70 preferentially binds to oligomeric as opposed to fibrillar tau aggregates and prevents anterograde FAT inhibition [31]

Evidence 8d0521be29

Previous findings indicate that Hsp70 prevents tau toxicity by preserving tau in its soluble form and preventing it from aggregating by binding to exposed hydrophobic residues [33]

Evidence d06b28cad5

It has also been demonstrated that Hsp70 can facilitate the degradation of pre-formed aggregates [33]

Evidence e47a5590ea

Tau reportedly exerts an effect on axonal transport by interfering and reducing the attachment frequency of the motor proteins to the microtubules [28]

Evidence 79b490c2a6

Furthermore, when Hsp70 was pre-incubated with the PAD peptide and introduced to the squid axoplasm, inhibition of FAT was still observed [31]

Evidence 22aa2f1a22

Deletion analyses demonstrate that FAT inhibition requires a small stretch of amino acids (residues 2–18) located within the N-terminus that we have termed the PAD (phosphataseactivation domain) [21]

Evidence c06009f2d2

Further investigation illustrated that this inhibition occurs via activation of a signalling cascade involving PP1 (protein phosphatase 1) and GSK3 (glycogen synthase kinase 3) [24]

Evidence cf0d83bf4f

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3]


BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.