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)
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]
AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau
Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect
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
However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21]
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
Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease
This indicates that tau oligomers represent the main toxic species responsible for neurodegeneration associated with AD
Time-course aggregation analysis revealed that dimerization precedes tau oligomerization which, in turn, is an earlier event than the formation of full-length filaments
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]
Tau’s primary role within neurons is thought to be the regulation and stabilization of microtubule dynamics [1,2]
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
However, our data indicate that Hsp70 preferentially binds to oligomeric as opposed to fibrillar tau aggregates and prevents anterograde FAT inhibition [31]
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]
It has also been demonstrated that Hsp70 can facilitate the degradation of pre-formed aggregates [33]
Tau reportedly exerts an effect on axonal transport by interfering and reducing the attachment frequency of the motor proteins to the microtubules [28]
Furthermore, when Hsp70 was pre-incubated with the PAD peptide and introduced to the squid axoplasm, inhibition of FAT was still observed [31]
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]
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]
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]
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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.