ERK (MAPK) does not phosphorylate tau under physiological conditions in vivo or in vitro.

Alzheimer's disease is characterized by the deposition of intracellular aggregates of hyperphosphorylated tau protein. Tau hyperphosphorylation has been attributed in part to the deregulation of kinases and phosphatases activities. Extracellular signal regulated-kinases 1/2 (ERK1/2) were reported to be activated in the first stages of Alzheimer's disease and were proposed as a potential therapeutic target. However, although the phosphorylation of tau by ERK1/2 has been demonstrated in cell-free system, it remains controversial in vivo. Here, we showed that pharmacologic inhibition of ERK1/2 in mice and SH-SY5Y cells did not reduce basal levels of phospho-tau or hypothermia-induced tau hyperphosphorylation. We also found that activating ERK1/2 by hyperthermia did not correlate with increased tau phosphorylation. Finally, ERK1/2 was inhibited, but tau phosphorylation was not altered in Mek1-/- mice. In conclusion, these results do not support the involvement of ERK1/2 in tau phosphorylation under physiological conditions.

Hypothermia-induced hyperphosphorylation: a new model to study tau kinase inhibitors.

Tau hyperphosphorylation is one hallmark of Alzheimer's disease (AD) pathology. Pharmaceutical companies have thus developed kinase inhibitors aiming to reduce tau hyperphosphorylation. One obstacle in screening for tau kinase inhibitors is the low phosphorylation levels of AD-related phospho-epitopes in normal adult mice and cultured cells. We have shown that hypothermia induces tau hyperphosphorylation in vitro and in vivo. Here, we hypothesized that hypothermia could be used to assess tau kinase inhibitors efficacy. Hypothermia applied to models of biological gradual complexity such as neuronal-like cells, ex vivo brain slices and adult non-transgenic mice leads to tau hyperphosphorylation at multiple AD-related phospho-epitopes. We show that Glycogen Synthase Kinase-3 inhibitors LiCl and AR-A014418, as well as roscovitine, a cyclin-dependent kinase 5 inhibitor, decrease hypothermia-induced tau hyperphosphorylation, leading to different tau phosphorylation profiles. Therefore, we propose hypothermia-induced hyperphosphorylation as a reliable, fast, convenient and inexpensive tool to screen for tau kinase inhibitors.