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

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Signaling

Background:

• Apolipoprotein E (apoE) peptide activates cytoplasmic Ca2+ influx and G-protein-coupled pathways in rat cortical neurons.
• Previous research established apoE peptide's role in modulating intracellular calcium levels.
• The effect of these calcium-associated pathways on tau protein phosphorylation remained unclear.

Purpose of the Study:

• To investigate if apoE peptide-induced signaling pathways affect the phosphorylation of microtubule-associated protein tau.
• To determine the specific phosphorylation sites on tau affected by apoE peptide treatment.
• To elucidate the roles of calcium influx and G-protein signaling in apoE-mediated tau dephosphorylation.

Main Methods:

• Primary rat cortical neurons were treated with a biologically active apoE synthetic peptide (apoEdp).
• Tau phosphorylation levels at Thr231, Ser235, and Ser396 were quantified using ELISA with specific monoclonal antibodies.
• Involvement of calcium influx, G-protein pathways, and specific protein phosphatases (PP2A, PP2B) was assessed using inhibitors like cyclosporin A and okadaic acid.

Main Results:

• ApoEdp treatment induced a concentration- and time-dependent dephosphorylation of tau at Thr231, Ser235, and Ser396.
• Dephosphorylation at Thr231 and Ser235 was dependent on extracellular Ca2+ influx.
• Dephosphorylation at Ser396 was mediated by a pertussis toxin-sensitive G-protein pathway, involving protein phosphatases 2A and 2B.

Conclusions:

• Apolipoprotein E peptide dephosphorylates tau protein at multiple sites in neurons.
• The apoE-induced tau dephosphorylation is mediated by distinct calcium-dependent and G-protein-dependent pathways.
• These pathways likely activate protein phosphatases 2A and 2B, leading to tau dephosphorylation.