Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy

Abstract

Aim-Tau protein is a prominent component of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. While the abnormal phosphorylation of tau on serine and threonine has been well established in the disease process, its phosphorylation on tyrosine has only recently been described. We previously showed that the Src family non-receptor tyrosine kinases (SFKs) Fyn and Src phosphorylate tau on Tyr18 and that phospho-Tyr18-tau was present in AD brain. In this study, we have investigated the appearance of phospho-Tyr18-tau, activated-SFK, and Proliferating Cell Nuclear Antigen (PCNA) during disease progression in a mouse model of human tauopathy.Methods-We have used JNPL3, which expresses human tau with P301L mutation, and antibodies specific for phospho-Tyr18-tau (9G3), ser/thr phosphorylated tau (AT8), activated-SFK, and PCNA. Antibody staining was viewed by either epifluorescence or confocal microscopy.Results-Phospho-Tyr18-tau appeared concurrently with AT8-reactive tau as early as 4 months in JNPL3. Some 9G3-positive cells also contained activated-SFKs and PCNA. We also investigated the triple transgenic mouse model of AD and found that unlike the JNPL3 model, the appearance of 9G3 reactivity did not coincide with AT8 in the hippocampus, suggesting that the presence of APP/presenilin influences tau phosphorylation. Also, thioflavin-S positive plaques were 9G3 negative, suggesting that phospho-Tyr18 tau is absent from the dystrophic neurites of the mouse triple transgenic brain.Conclusions-Our results provide evidence for the association of tyrosine-phosphorylated tau with mechanisms of neuropathogenesis and indicate that SFK activation and cell cycle activation are also involved in JNPL3.

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…receptor tyrosine kinase family member Fyn that increases during disease progression (31). However, consistent with the Tau dephosphorylation data, ADx215 shows a preference for nonphosphorylated Tyr 18 ( Fig.…”

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

“…We show that treatment of SH-SY5Y cells with the selective Syk inhibitor BAY61-3606 results in a partial reduction of Tau phosphorylation at Tyr-18 but also an almost complete inhibition of Tau phosphorylation at Ser-202 (CP13) and Ser-396/Ser-404 (PHF-1). The partial inhibition of Tau phosphorylation at Tyr-18 following Syk inhibition may be explained by the fact that other tyrosine kinases are also known to phosphorylate Tau at this particular residue (71). Additionally, we show that treatment of Tg Tau P301S mice with the selective Syk inhibitor BAY61-3606 results in a reduction of Tau Tyr-18 phosphorylation as expected but also in a significant decrease in Tau phosphorylation at other epitopes, including Ser-202 (CP13) and Ser-396/ Ser-404 (PHF-1) that are phosphorylated by GSK3␤ (13).…”

“…Syk has also been shown to phosphorylate Tau in vitro, primarily at the Tyr-18 residue (56), which is considered to be an early event in the pathophysiology of AD (56,71). We show that treatment of SH-SY5Y cells with the selective Syk inhibitor BAY61-3606 results in a partial reduction of Tau phosphorylation at Tyr-18 but also an almost complete inhibition of Tau phosphorylation at Ser-202 (CP13) and Ser-396/Ser-404 (PHF-1).…”

Tau-induced neurodegeneration: mechanisms and targets

“…Abl is known to phosphorylate tyrosine 394 (Y394) and, recently, the Tyr kinase Arg, which plays a role in the oxidative stress response and neuronal development, was also shown to phosphorylate Y394 in a manner independent of Abl activity [55] . In a transgenic mouse model of AD, tyrosine 18-phosphorylated tau occurs in neurofibrillary tangles and the expression of Fyn is increased in these cases [56,57] . From these data it appears that Fyn, c-Abl, and Arg are critical kinases in the neurodegenerative process.…”