Dephosphorylation of tau during transient forebrain ischemia in the rat

Abstract

The effect of transient cerebral ischemia on phosphorylation of the microtubule-associated protein (MAP) tau was investigated using the rat four-vessel occlusion model. Phosphorylation of tau is proposed to regulate its binding to microtubules, influencing the dynamics of microtubule assembly necessary for axonal growth and neurite plasticity. In this study, tau was rapidly dephosphorylated during ischemia in the hippocampus, neocortex, and striatum. Dephosphorylation of tau was observed within 5 min of occlusion and increased after 15 min in all three brain regions, regardless of their relative vulnerability to the insult. Thus, dephosphorylation of tau is an early marker of ischemia and precedes the occlusion time required to cause extensive neuronal cell death in this model. On restoration of blood flow for a little as 15 min, tau was phosphorylated at a site(s) that causes a reduction in its electrophoretic mobility. The dephosphorylation/phosphorylation of tau may alter its distribution between axon and cell body, and affect its susceptibility to proteolysis. These changes would be expected to influence microtubule stability, possibly contributing to disruption of axonal transport, but also allowing neurite remodeling in a regenerative response.

Microglial tau undergoes phosphorylation‐independent modification after ischemia

“…5). Experimental data on cultured cells or animal models have demonstrated that tau proteins are transiently dephosphorylated but never hyperphosphorylated during ischemia and reperfusion or similar experimental conditions (Dewar and Dawson, 1995;Shackelford and Nelson, 1996;Burkhart et al, 1998;Shackelford and Yeh, 1998). It is therefore probable that tau protein in ischemic foci undergoes some pathological modifications to be visualized on immunohistochemistry, although these modifications are not necessarily related to phosphorylation and are indistinguishable from unmodified human tau protein on routine immunoblot, as we demonstrated on GCIs (Shibuya et al, 2003).…”

Differential Changes in Phosphorylation of Tau at PHF-1 and 12E8 Epitopes During Brain Ischemia and Reperfusion in Gerbils

“…In comparison, regulation of the 12E8 site appears to be less dependent on ATP/GTP levels. In rats, occlusion of the middle cerebral artery causes rapid dephosphorylation of tau as demonstrated by changes in the mobility or immunoreactivity of tau protein [20,38]. Dephosphorylation rate may depend on the specific phosphorylation site and localization of tau.…”

“…Rapid dephosphorylation of tau has been reported in post mortem rat and human brain tissues [17,18] indicating that phosphorylation state of tau is a very dynamic process. The effects of ischemia and reperfusion on tau metabolism have been studied in rats [19,20] and dogs [21] but not in gerbils. Yet gerbils are a long established model of reversible ischemia [22][23][24] used in a number of biochemical studies [1][2][3][4][5].…”

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Required for the Development of Ischemic Neuronal Death

“…Although tau phosphorylation was not examined here, it is noteworthy that changes in tau phosphorylation have been observed during cardiac arrest-induced cerebral ischemia and reperfusion (Mailliot et al, 2000), transient forebrain ischemia in rats (Shackelford and Yeh, 1998), and in cortical slices subjected to hypoxia combined with glucose deprivation (Burkhart et al, 1998).…”