Premium
O1‐06–04: Methylthioninium chloride (MTC) acts as a Tau aggregation inhibitor (TAI) in a cellular model and reverses Tau pathology in transgenic mouse models of Alzheimer's disease
Author(s) -
Harrington Charles,
Rickard Janet E.,
Horsley David,
Harrington Kathleen A.,
Hindley Kathleen P.,
Riedel Gernot,
Theuring Franz,
Seng Kwang Meng,
Wischik Claude M.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.259
Subject(s) - entorhinal cortex , hippocampus , genetically modified mouse , subiculum , chemistry , cortex (anatomy) , neuroscience , senile plaques , amygdala , retrosplenial cortex , pathology , alzheimer's disease , microbiology and biotechnology , biology , transgene , biochemistry , medicine , dentate gyrus , disease , gene
much is known about different tau kinases, phosphatases and phosphorylation sites the mechanism of neurodegeneration has been elusive. We have previously shown that the cytosolic Alzheimer hyperphosphorylated tau (AD P-tau) sequesters normal tau, MAP1A, MAP1B and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Objective: To study the influence of tau phosphorylation at Ser 199, Thr 212, Thr 231, Ser 262, Ser 396 alone or in combination for tau-tau binding, self-assembly and the effect of its expression on the cells. Methods: Pseudophosphorylated tau was generated by site directed mutagenesis. Pseudophosphorylated tau was transiently expressed in PC12 cells and in CHO cells. The effect of expression of mutated taus on self assembly and binding to microtubules was studied by immunocytochemistry. Binding of normal tau to pseudophosphorylated tau was studied by dot overlay assays. Caspase activation and apoptosis were determined by immunocytochemistry after transient transfection. Results: We found that pseudophosphorylated tau aggregates in cells when Thr 212 is mutated to Glu, suggesting that phosphorylation at this site facilitates tau self-assembly. The expression of tau pseudophosphorylated at Thr212, Thr231, and Ser262 triggers caspase 3 activation in as much as 85% of the transfected cells and apoptosis to a lesser degree. Conclusions: These findings suggest that tau phosphorylation at Thr 212 facilitates tau self-aggregation, and that the combination of phosphorylation at Thr212, 231 and Ser262 in the same tau molecule can trigger toxic reaction. Pseudophosphorylated tau, as Alzheimer phosphorylated tau, sequesters normal tau.