Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies

Abstract

Calcium/calmodulin-dependent kinase II (alpha- and beta-CaM kinase II), and phosphorylated mitogen-activated extracellular signal-regulated protein kinase (MAPK/ERK-P), phosphorylated protein kinase of 38 kDa (p38-P) and phosphorylated stress-activated protein kinase (SAPK/JNK-P) expression have been examined in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The study was carried out to increase understanding of the signals that may regulate tau phosphorylation in tauopathies. MAPK/ERK-P was found in a subset of neurons and glial cells bearing abnormal tau deposition, but rarely in neurofibrillary tangles. Strong p38-P immunoreactivity was observed in about 50-70% of neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques in AD. Strong p38-P immunoreactivity was seen in practically all Pick bodies in PiD, and in most neurons with neurofibrillary degeneration or with tau deposits (pre-tangle neurons) in PSP and CBD, as revealed with single and double-labeling immunohistochemistry to p38-P and tau. In addition, strong p38-P immunoreactivity was present in tau-positive astrocytes and in coiled bodies in PSP and CBD. Single and double-labeling immunohistochemistry to MAPK/ERK-P and p38-P disclosed that MAPK/ERK-P appeared at early stages of tau phosphorylation in neurons and glial cells in tauopathies, and that MAPK/ERK-P and p38-P co-localize only in a subset of neurons and glial cells with phosphorylated tau deposits. SAPK/JNK-P immunoreactivity was seen in a subset of neurons, including many neurons with neurofibrillary degeneration, and in glial cells accumulating abnormal tau, in AD, PiD, PSP and CBD. Double-labeling immunohistochemistry disclosed partial co-localization of SAPK/JNK-P and either MAPK/ERK-P or p-38-P immunoreactivity. These findings indicate that MAPK/ERK-P, SAPK/JNK-P and p-38-P are differentially expressed in association with tau deposits in tauopathies. Finally, CaM kinase II is present in neurons but not in glial cells, thus suggesting no role of CaM kinase II in tau phosphorylation of glial cells. These observations, together with previous results of in vitro studies, support the idea that several MAPK/ERK, SAPK/JNK, p38 and CaM kinase II may participate in tau phosphorylation in tauopathies. Lack of co-localization between MAPK/ERK-P, SAPK/JNK-P and p-38-P over-expression, and staining with the method of in situ end-labeling of nuclear DNA fragmentation in individual cells indicate that over-expression of these kinases is not linked with increased nuclear DNA vulnerability in AD, PiD, PSP and CBD.

Down-regulation of WW Domain-containing Oxidoreductase Induces Tau Phosphorylation in Vitro

“…Phosphorylated ERK, p38, JNK1, and calmodulin kinase II are differentially expressed in Tau deposits in neurons and glial cells in tauopathies (18,19). We determined that WOX1 physically interacted with Tau, JNK1, and GSK-3␤ in the extracts of rat brains and cultured cells (data not shown for rat brains).…”

Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons

“…Schievella et al (11) report that DENN overexpression in nonneuronal culture systems results in activation of both extracellular-regulated kinase (ERK) and JNK. However, because MAPKs are activated in AD (42), and DENN and TRAF2 are down-regulated, it is not likely that these proteins contribute to JNK-or ERK-mediated cell death or survival pathways.…”

Astrogliopathy in Tauopathies

“…Astrocytes containing hyper-phosphorylated tau inclusions co-express phosphorylated tau kinases: mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), p-38 kinase, stress-activated kinase/c-Jun N-terminal kinase (SAPK/JNK) and glycogen synthase kinase-3 [14,82,[96][97][98][99][100]. Co-expression in astrocytes suggests active phosphorylation of tau by specific kinases; such co-localization also occurs in neurons with pre-tangles and tangles in the same tauopathies.…”