Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways

• Published in: Journal of neuroscience research 1998-03, Vol.51 (5), p.658-665
• Main Authors: Wang, Xiao-shu, Luebbe, Patricia, Gruenstein, Eric, Zemlan, Frank
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antifungal Agents - pharmacology; apolipoprotein E; Apolipoproteins E - metabolism; Calcium - metabolism; Cyclosporine - pharmacology; Cytoplasm - metabolism; cytoplasmic calcium; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; G-protein; Immunosuppressive Agents - pharmacology; Molecular Sequence Data; neurons; Neurons - chemistry; Neurons - enzymology; Okadaic Acid - pharmacology; Peptide Fragments - metabolism; Phosphoric Monoester Hydrolases - antagonists & inhibitors; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; protein phosphatase; Pyrans; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Signal Transduction - physiology; Spiro Compounds; tau; tau Proteins - immunology; tau Proteins - metabolism; Time Factors; Virulence Factors, Bordetella - pharmacology
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/(SICI)1097-4547(19980301)51:5<658::AID-JNR13>3.0.CO;2-Z

Previous studies have shown that treating rat cortical neurons in primary culture with apolipoprotein E (apoE) peptide increased cytoplasmic Ca2+ by 2 mechanisms: 1) an influx of extracellular Ca2+ resulting from the activation of a cell surface Ca2+ channel; and 2) release of Ca2+ from internal Ca2+ stores via a G‐protein‐coupled pathway (Wang and Gruenstein, 1997). These studies employed a biologically active apoE synthetic peptide (apoEdp) 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. ApoEdp treatment resulted in a concentration‐ and time‐dependent dephosphorylation of tau at all 3 phosphorylation sites. The apoEdp‐induced dephosphorylation of tau at thr231, and ser235 was dependent on the influx of extracellular Ca2+, while dephosphorylation at ser396 was mediated by a pertusis toxin‐sensitive G‐protein pathway. The involvement of protein phosphatases in mediating the apoEdp‐induced dephosphorylation of tau was examined. Pretreatment with the protein phosphatase 2B inhibitor cyclosporin A blocked the apoEdp‐induced dephosphorylation of tau at thr231 and ser235 but not at ser396. Pretreatment with the protein phosophatase 2A/1 inhibitor okadaic acid blocked the apoEdp‐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 Ca2+‐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.