Sci Rep. 2015 Jun 29;5:11765. doi: 10.1038/srep11765.
Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β.
Abstract
Abnormal
tau hyperphosphorylation is an early pathological marker of Alzheimer's
disease (AD), however, the upstream factors that regulate tau
phosphorylation are not illustrated and there is no efficient strategy
to arrest tau hyperphosphorylation. Here, we find that activation of
endogenous EphB2 receptor by ligand stimulation (ephrinB1/Fc) or by
ectopic expression of EphB2 plus the ligand stimulation induces a
remarkable tau dephosphorylation at multiple AD-associated sites in
SK-N-SH cells and human embryonic kidney cells that stably express human
tau (HEK293-tau). In cultured hippocampal neurons and the hippocampus
of human tau transgenic mice, dephosphorylation of tau proteins was also
detected by stimulation of EphB2 receptor. EphB2 activation inhibits
glycogen synthase kinase-3β (GSK-3β), a crucial tau kinase, and
activates phosphatidylinositol-3-kinase (PI3K)/Akt both in vitro and in
vivo, whereas simultaneous inhibition of PI3K or upregulation of GSK-3β
abolishes the EphB2 stimulation-induced tau dephosphorylation. Finally,
we confirm that ephrinB1/Fc treatment induces tyrosine phosphorylation
(activation) of EphB2, while deletion of the tyrosine kinase domain (VM)
of EphB2 eliminates the receptor stimulation-induced GSK-3β inhibition
and tau dephosphorylation. We conclude that activation of EphB2 receptor
kinase arrests tau hyperphosphorylation through PI3K-/Akt-mediated
GSK-3β inhibition. Our data provide a novel membranous target to
antagonize AD-like tau pathology.
- PMID:
- 26119563
- PMCID:
- PMC4484244
- DOI:
- 10.1038/srep11765
- [Indexed for MEDLINE]
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