This paper describes an extremely important and exciting result that clearly demonstrates for the first time that both human tau as well as the Drosophila homolog of GSK3b, (a kinase implicated in abnormal tau phosphorylation) are essential for neurofibrillary pathology and neurodegeneration phenotype in Drosophila.

In the current study, Jackson et al. overexpressed wild-type human 4-repeat tau. This resulted in neurodegeneration, as observed previously in Drosophila. However, when they expressed shaggy, a Drosophila homolog of GSK3b, the neurodegeneration was exacerbated. More importantly, it resulted in the formation of filamentous tau aggregates that are similar to the neurofibrillary tangles observed in Alzheimer's disease. Furthermore, the authors observed a correlation between the severity of neurodegeneration and the presence of hyperphosphorylated tau. In mice, Avila and colleagues have shown that inducible expression of GSK3b leads to tau hyperphosphorylation and neurodegeneration in hippocampus (  Read more

This paper describes an extremely important and exciting result that clearly demonstrates for the first time that both human tau as well as the Drosophila homolog of GSK3b, (a kinase implicated in abnormal tau phosphorylation) are essential for neurofibrillary pathology and neurodegeneration phenotype in Drosophila.

In the current study, Jackson et al. overexpressed wild-type human 4-repeat tau. This resulted in neurodegeneration, as observed previously in Drosophila. However, when they expressed shaggy, a Drosophila homolog of GSK3b, the neurodegeneration was exacerbated. More importantly, it resulted in the formation of filamentous tau aggregates that are similar to the neurofibrillary tangles observed in Alzheimer's disease. Furthermore, the authors observed a correlation between the severity of neurodegeneration and the presence of hyperphosphorylated tau. In mice, Avila and colleagues have shown that inducible expression of GSK3b leads to tau hyperphosphorylation and neurodegeneration in hippocampus (Lucas et al. 2001).

These results provide unequivocal evidence that abnormal tau phosphorylation per se is essential for initiating neurodegeneration. They also identify shaggy/GSK3b as an excellent candidate for mediating NFT formation in Drosophila. Modulation of downstream effectors of GSK3b in the wnt pathway, such as armadillo/b-catenin or pangolin/TCF, demonstrated that loss-of-function mutations suppressed while overexpression enhanced the tau-induced neurodegeneration. This supports the observation that GSK3b/shaggy is exerting its effects via direct tau phosphorylation rather than via the wnt pathway.

This study provides critical support for therapeutic opportunities aimed at targeting proteins that lead to tauopathies. Obviously the next steps will include the use of inhibitors to reverse the observed phenotype."

View all comments by Ratan Bhat

"Some excitement is in order following the Jackson et al study but commenter Rathan Bat should be reminded of some facts. Our experience in transgenic mice, and work by others in knockout mice, shows that extreme levels of GSK-3b are lethal, that is, both its absence and its overexpression (Spittaels et al., 2000; Spittaels et al., 1999; and work in press). You and I are living witness to the fact that intermediate levels are acceptable.

It is not clear in the current Drosophila study what exactly the GSK-3b levels were in the flies? Are they "physiological" or rather, like many overexpression systems, highly un-physiological? Are they in any way similar to the levels in the brain of healthy humans or AD patients?

GSK-3b was shown long ago to be a tau kinase in vitro, then we and others proved this in vivo in mammalian brain (Spittaels et al, 1999, 2000; Lucas et al., 2001). This is now once more confirmed in the fly. Not clear in any system is precisely...  Read more

"Some excitement is in order following the Jackson et al study but commenter Rathan Bat should be reminded of some facts. Our experience in transgenic mice, and work by others in knockout mice, shows that extreme levels of GSK-3b are lethal, that is, both its absence and its overexpression (Spittaels et al., 2000; Spittaels et al., 1999; and work in press). You and I are living witness to the fact that intermediate levels are acceptable.

It is not clear in the current Drosophila study what exactly the GSK-3b levels were in the flies? Are they "physiological" or rather, like many overexpression systems, highly un-physiological? Are they in any way similar to the levels in the brain of healthy humans or AD patients?

GSK-3b was shown long ago to be a tau kinase in vitro, then we and others proved this in vivo in mammalian brain (Spittaels et al, 1999, 2000; Lucas et al., 2001). This is now once more confirmed in the fly. Not clear in any system is precisely how GSK-3b acts. Moreover, previous studies showed neurodegeneration in the fly caused by tau without any tangle formation. Also in mice, neurodegeneration due to AβPP does not require amyloid plaques per se.

Taken together, all these data free us from the dogma that models must show plaques and tangles to be informative. Quite the opposite: I expect that models that do not show the classical AD lesions but "pre-pathological stages" will become more informative. On the other hand, the fact that the wingless pathway is not involved in the fly—or was it ?—only makes the problem harder to understand."

View all comments by Fred Van Leuven