Agonist Antibody

Tau phosphorylation sites seem to be turned over rapidly in normal brain in a cyclical process catalysed by the concerted actions of protein kinases and phosphatases.In the tauopathies, it seems that this cycle becomes frozen, or at least the balance is tipped in favour of phosphorylated tau, resulting in the appearance of abnormal tau in an Hesperidin enhanced and more stable state of phosphorylation.This highly phosphorylated material seems to build up gradually into characteristic intracellular aggregates of tau.The number of phosphorylated residues present in tau from AD brain exceeds that detected during development, estimated at sites in tau extracted from foetal rat brain, although the overall stoichiometry of phosphorylation is reported to be similar in AD and foetal tau. This direct identication of multiple phosphorylation sites in tau from embryonic brain is in keeping with reports of increased tau phosphorylation identied using phosphospecic tau antibodies during periods of increased synaptic plasticity. Multiple kinases are likely to be involved in generating phosphorylated tau A comparison of the patterns of phosphorylation sites on tau extracted from normal and AD brain with sites identied on recombinant human tau by candidate tau kinases indicates the likelihood of more than one kinase being involved in tau phosphorylation.This is important because current therapeutic strategies are aimed at specic and complete inhibition of individual tau kinases and offtarget kinase inhibition is regarded as disadvantageous to drug Losartan discovery.One possibility is that tau might be primed by one kinase before subsequent phosphorylation by a second kinase that recognizes a nearby phosphorylated residue.In the case of tau, dualspecicity tyrosinephosphorylation regulated kinase A and cdk have been suggested to act as priming kinases for subsequent GSK phosphorylation. However, formal proof for in vivo priming of tau by these kinases is currently lacking.Furthermore, activation of one kinase might induce increased activity of related tau kinases, resulting in a kinase cascade.Interactions between cdk and kinases that phosphorylate neurolaments have also been reported, with resulting changes in phosphorylation at specic sites, highlighting the need to investigate the potential for indirect effects of kinase inhibition on target substrates. Numerous interactions between protein serinethreonine have been reported.These should be considered in the design of therapeutic strategies involving kinase inhibition.As indicated by, inhibition or knockout of cdk activates GSK.Dashed and solid lines indicate indirect and direct interactions, respectively, and red lines indicate inhibitory relationships between enzymes.There is therefore a need to identify valid systems in cells and animals that can address the issue.In particular, a cellular model of tau aggregation is needed that accurately mimics the accumulation of tau in brain tauopathy because this would have the potential for pharmacological intervention.It remains to be seen whether targeting specific kinases or distinct cohorts of kinases is more effective at reducing tau phosphorylation in the tauopathies.However, reciprocal interplay between kinases such as cdk and GSK has been demonstrated in models of AD, indicating that this approach will need careful validation. It has been presumed that tau phosphorylation is a prerequisite for its aggregation, although this has yet to be proven.An alternative possibility is that tau aggregates before becoming phosphorylated, leaving it in a conformationally altered state that could protect the deposited tau from the action of protein phosphatases.

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