Current Advances on Different Kinases Involved in Tau Phosphorylation, and Implications in Alzheimers Disease and Tauopathies

Abstract

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

The involvement of glycogen synthase kinase‐3 and protein phosphatase‐2A in lactacystin‐induced tau accumulation

“…It was also reported previously that proteasome inhibition by MG-132, a reversible proteasome inhibitor, stabilizes tau inclusions in oligodendroglial cells treated with okadaic acid [34]. As a more obvious accumulation of the hyperphosphorylated tau was observed in HEK293/441 cells during protea- some inhibition, we measured the activity of GSK-3, a crucial tau kinase [5]. We observed that the activity of GSK-3 was significantly increased after treatment of the cells with lactacystin.…”

“…Among various kinases and phosphatases, glycogen synthase kinase-3 (GSK-3) and protein phosphatase-2A (PP-2A) are, respectively, the crucial kinase and phosphatase for the ADlike tau hyperphosphorylation [5][6][7].…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Recent studies suggested mitogen-activated protein kinases (MAPKs) as key regulators of the formation of plaques and tau hyperphosphorylation in AD (147). MAPKs pathways transduce intracellular signaling to increase expression of different proteins; dysregulation of MAPK-dependent pathways suggests a systematic disorder of protein translation regulation in MCI brains.…”

Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development

“…Moreover, GSK-3b has been shown to regulate cyclin D1 proteolysis and subcellular localization in mouse fibroblasts (Diehl et al 1998). GSK-3 has also been implicated in Alzheimer's disease (Ferrer et al 2005). In the present study, we have investigated how GSK-3a and GSK-3b are regulated by soluble KL in cultured growing mouse oocytes, and suggest that GSK-3 may play a role in oocyte growth and early follicular development.…”