Role of GSK3beta in tau phosphorylation

The tauopathies, including Alzheimer’s disease (AD), are characterised by aggregation of tau, particularly in neurons. This aggregation of tau into neurofibrillary tangles is accompanied by increased phosphorylation although it remains to be determined whether tau phosphorylation is a primary or secondary process. One suggestion is that highly phosphorylated tau fails to bind efficiently to microtubules, accumulates in cytoplasm and consequently aggregates; a suggestion in line with the finding of loss of microtubules in affected neurons. This hypothesiswould predict loss of microtubule function and alterations in axonal transport early in AD. Certainly, both phosphorylation and mutation of tau reduce tau function with respect to microtubule binding. In order to examine further the role of phosphorylation in the function of tau in relation to axonal transport we have generated models for studying axonal transport in mammalian neurons and in Drosophila. These have enabled us to directly visualise the effect of tau phosphorylation on axonal transport in an in vivo system for the first time Furthermore, we and others, have demonstrated that tau phosphorylation can be regulated by both wnt and insulin signalling. Both processes decrease tau phosphorylation and increase non-amyloidogenic APP metabolism.We therefore hypothesised that polymorphic variation in genes on these pathways are prime candidates for susceptibility loci in AD. Thus farwe have identified variation in genes in the wnt signalling pathway that are not associated with AD whereas polymorphic variation in insulin signalling is associated with AD, at least in women. These data suggest that the observed association between insulin resistance and AD might be mediated through increased tau phosphorylation, failing tau function and resulting tau accumulation and aggregation and that the regulation of tau phosphorylation is critical in AD pathogenesis suggesting new therapeutic opportunities in AD.