Nitric oxide induces tau hyperphosphorylation via glycogen synthase kinase‐3β activation

Abstract

Nitric oxide is associated with neurofibrillary tangle, which is composed mainly of hyperphosphorylated tau in the brain of AlzheimerÕs disease (AD). However, the role of nitric oxide in tau hyperphosphorylation is unclear. Here we show that nitric oxide produced by sodium nitroprusside (SNP), a recognized donor of nitric oxide, induces tau hyperphosphorylation at Ser396/404 and Ser262 in HEK293/tau441 cells with a simultaneous activation of glycogen synthase kinase-3b (GSK-3b). Pretreatment of the cells with 10 mM lithium chloride (LiCl), an inhibitor of GSK-3, 1 h before SNP administration inhibits GSK-3b activation and prevents tau from hyperphosphorylation. This is the first direct evidence demonstrating that nitric oxide induces AD-like tau hyperphosphorylation in vitro, and GSK3b activation is partially responsible for the nitric oxide-induced tau hyperphosphorylation. It is suggested that nitric oxide may be an upstream element of tau abnormal hyperphosphorylation in AD.

Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3β constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines

“…This resulted in a significant GSK3b dephosphorylation and massive loss of BsB8 cells in monolayer cultures. Of interest, SNP which is clinically approved antihypertensive agent (Cheng et al, 2005), and serves as a donor of nitric oxide, has been also found as a potent GSK3b activator (Zhang et al, 2005). In this respect, recent reports have shown a strong SNP-mediated cytotoxicity against different tumor cell lines in vitro (Blackburn et al, 1998;Chao et al, 2004), and our study also has demonstrated its effectiveness, in combination with IGF-IR inhibition, against otherwise resistant human medulloblastoma cell line, D384 (Figure 7).…”

“…The SNP treatment has recently been found to cause the dephosphorylation of the serine 9 residue of GSK3b (Zhang et al, 2005). Indeed, results in Figure 6c indicate that the presence of SNP efficiently decreased GSK3b phosphorylation at this site.…”

Impaired functions of neural stem cells by abnormal nitric oxide-mediated signaling in an in vitro model of Niemann-Pick type C disease

“…Moreover, NO induces tau hyperphosphorylation via GSK3β activation [21]. The inactivation of GSK3β has been shown to correlate with reduced degeneration in vivo [38].…”

“…Over-expression of GSK3β has been shown to induce apoptosis through the activation of caspase-3 [19][20][21]. We investigated the levels of GSK3β activity by its phosphorylation status.…”

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

“…Excessive NO production by iNOS is also a contributory factor in the onset of septic shock [9]. Over active nNOS can result in hyperphosphorlyation and accumulation of tau proteins, an event which has been implicated in Alzheimer's disease [24,25]. In addition oxidative damage caused by over active nNOS leads to dysregulation of the signalling pathways and has long been associated with a variety of neurological conditions including Parkinson's disease [26,27].…”