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Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways
Author(s) -
Wang Xiaoshu,
Luebbe Patricia,
Gruenstein Eric,
Zemlan Frank
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19980301)51:5<658::aid-jnr13>3.0.co;2-z
Subject(s) - dephosphorylation , phosphorylation , okadaic acid , phosphatase , signal transduction , chemistry , extracellular , biochemistry , tau protein , apolipoprotein e , microbiology and biotechnology , biology , medicine , alzheimer's disease , disease
Previous studies have shown that treating rat cortical neurons in primary culture with apolipoprotein E (apoE) peptide increased cytoplasmic Ca 2+ by 2 mechanisms: 1) an influx of extracellular Ca 2+ resulting from the activation of a cell surface Ca 2+ channel; and 2) release of Ca 2+ from internal Ca 2+ stores via a G‐protein‐coupled pathway (Wang and Gruenstein, 1997). These studies employed a biologically active apoE synthetic peptide (apoE dp ) derived from the receptor binding domain of apoE. In the present study we examined whether activation of these 2 signal transduction pathways affects phosphorylation of microtubule‐associated protein tau. The levels of tau phosphorylation at thr231, ser235, and ser396 were quantified by ELISA employing monoclonal antibodies PHF‐6, SMI33, and PHF‐1. ApoE dp treatment resulted in a concentration‐ and time‐dependent dephosphorylation of tau at all 3 phosphorylation sites. The apoE dp ‐induced dephosphorylation of tau at thr231, and ser235 was dependent on the influx of extracellular Ca 2+ , while dephosphorylation at ser396 was mediated by a pertusis toxin‐sensitive G‐protein pathway. The involvement of protein phosphatases in mediating the apoE dp ‐induced dephosphorylation of tau was examined. Pretreatment with the protein phosphatase 2B inhibitor cyclosporin A blocked the apoE dp ‐induced dephosphorylation of tau at thr231 and ser235 but not at ser396. Pretreatment with the protein phosophatase 2A/1 inhibitor okadaic acid blocked the apoE dp ‐induced dephosphorylation of tau at all 3 sites, while pretreatment with the protein phosphates 1 inhibitor tautomycin was without effect. The present study suggests that apoE may affect several Ca 2+ ‐associated signal transduction pathways that increase the activity of protein phosphatases 2A and 2B, which in turn dephosphorylate tau. J. Neurosci. Res. 51:658–665, 1998. © 1998 Wiley‐Liss, Inc.