Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state.

Abstract

The microtubule‐associated protein tau is a major component of the paired helical filaments (PHFs) observed in Alzheimer's disease brains. The pathological tau is distinguished from normal tau by its state of phosphorylation, higher apparent M(r) and reaction with certain antibodies. However, the protein kinase(s) have not been characterized so far. Here we describe a protein kinase from brain which specifically induces the Alzheimer‐like state in tau protein. The 42 kDa protein belongs to the family of mitogen activated protein kinases (MAPKs) and is activated by tyrosine phosphorylation. It is capable of phosphorylating Ser‐Pro and Thr‐Pro motifs in tau protein (approximately 14–16 P1 per tau molecule). By contrast, other proline directed Ser/Thr kinases such as p34(cdc2) combined with cyclin A or B have only minor effects on tau phosphorylation. We propose that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.

Shift from fetal‐type to Alzheimer‐type phosphorylated Tau proteins in SKNSH‐SY 5Y cells treated with okadaic acid

“…This would support the idea of the existence of different states of phosphorylation of the same isoform. Such a hypothesis is compatible with (i) the observation reported by Ksiezak-Reding et al [22] that phosphatase treatment of PHF-Tau proteins induced a relative increase in the immunoreactivity of Tau 64 polypeptide and a decrease in the immunoreactivity of the Tau 69 band; and (ii) a multiple step phosphorylation of Tau proteins by in vitro kinase assays [7,10].…”

“…Some purified members of the proline-directed protein kinase family (MAP kinase, cyclin-dependent kinase, GSK3 kinase) were successfully tested for their capacity to phosphorylate in vitro Tau proteins and to generate Alzheimertype epitopes [7][8][9][10][11][12]. The molecular weight of in vitro phosphorylated Tau protein and PHF-Tau triplet was only compared in the two following systems.…”

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…However, sustained ERK1/2 activation has been associated with neuronal death (Alessandrini et al, 1999;Murray et al, 1998;Runden et al, 1998). Abnormal activation of the ERK1/2 pathway has also been implicated in the pathogenesis of Alzheimer's disease (Alessandrini et al, 1999;Drewes et al, 1992;Knowles et al, 1999;Perry et al, 1999;Trojanowski et al, 1993;Veeranna et al, 1998). In our studies, the level of activated and total ERK1/2 was increased but there was no evidence supporting a negative effect of the elevated levels on the hippocampal cultures.…”

p42 map kinase phosphorylation sites in microtubule‐associated protein tau are dephosphorylated by protein phosphatase 2A1 Implications for Alzheimer's disease

“…Each of these serines is followed by a proline, suggesting that protein kinases or protein phosphatases with specificity for phosphoseryi-proline may be involved. Recently, a protein kinase with the characteristics of a mitogen-activated protein (MAP) kinase was purified from pig brain and shown to phosphorylate recombinant tr.u to en Alzheitner-like state, as evidenced by a reduction i;r gel mobility and the phosphorylation of serine/threonineproline sites [9]. Moreover, two brain protein kinases (PK36 and PK40) phosphorylate tau at serine-396 and other serine/threonine-proline sites [IO] and a kinase called tau protein kinase I also phosphorylates tau at some scrine/threonine-proline sites [l I].…”