However, to date there is no clear evidence that phosphorylation is necessary or sufficient for tau-mediated neurodegeneration. Based on the hypothesis that hyperphosphorylation of tau is an early driver of tau pathology, one of the initial therapeutic approaches was to target kinases, which were seen as a traditional drug target in the oncology field. Drug screenings were practical and straight forward, therefore, several kinase inhibitors were developed and moved into human trials. Numerous of publications implicate protein kinases with pathological phosphorylation of tau in AD, including glycogen synthase kinase 3 beta (GSK-3β), Fyn, and Abl, among others. [40,41] However, even if phosphorylation plays a role in toxicity, developing specific and safe kinase inhibitors is extremely challenging specially for long term treatment needed for Tauopathies. Moreover, even if phosphorylation is a critical it is still unclear which kinase is responsible or if there is a single or multiple kinases.
