Nonetheless, lithium, as well as some of newer synthetic GSK3 inhibitors, have been used in several tau transgenic drosophila83,84 and mouse models, and there are reports of reductions

in tau phosphorylation and aggregation.85,86 Whether the newer inhibitors will make it into clinical trials is uncertain. GSK3 is involved in many numerous cellular processes, including glycogen Inhibitors,research,lifescience,medical storage, control of cell division, and perhaps neuronal polarity There is an obvious concern about the potential for side effects from inhibition of this kinase. Sodium valproate is apparently being tested in a large clinical trial in Alzheimer’s disease patients87 although no data are yet published. Among the remaining candidate protein kinases, there is great interest in CDK5, the activity of which appears to play a very important role in brain development.88 Transgenic mice in which CDK5 activity Inhibitors,research,lifescience,medical is activated (by overexpression of the p25 activator) in adult brain show evidence of a striking neurodegeneration with some tau pathology.89,90 It has been reported that the concentration of p25 is elevated in the

human AD brain,91 although the validity of Inhibitors,research,lifescience,medical the original report has been questioned.92 Inhibitors of CDK5 appear to have some influence on the development of pathology in some tau transgenic Inhibitors,research,lifescience,medical mice, although the effects reported are not large.93 There are as yet no reports of the use of CDK5 inhibitors in humans. Finally, activated ERK2 has been reported to be cell assay associated with neurofibrillary tangles in human Alzheimer’s disease.94 A rather nonspecific inhibitor of this kinase was used in tau transgenic mice, with apparently some beneficial results,95 but as with GSK3 and CDK5, there are concerns that the multifaceted role of this kinase in cellular metabolism would appear to

lower the probability that such inhibitors will make it into human studies. One of the largest barriers to work Inhibitors,research,lifescience,medical of this GSK-3 type has been the lack of good research tools. Compounds that can specifically inhibit the activity of a single kinase (eg, GSK3β) and can efficiently cross the blood-brain barrier would allow better definition of the kinases that phosphorylate tau in vivo. There are few such compounds available to the research community. Precise definition of the kinases responsible for tau phosphorylation in the normal adult brain would be very helpful. As indicated above, there are a large number of different transgenic animal (and fly) models in which tau appears to be hyperphosphorylated, but it has been very difficult to dissect the signal transduction pathways responsible for this phosphorylation in any given model.