Apolipoprotein E and β‐amyloid (1–42) regulation of glycogen synthase kinase‐3β

Abstract

Glycogen synthase kinase-3β (GSK-3β) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and β-amyloid (Aβ) 1–42 on GSK-3β and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca²⁺-independent and early activation of GSK-3β. ApoE4 effects were biphasic, with an early strong GSK-3β activation that was partially dependent on extracellular Ca²⁺, followed by a GSK-3β inactivation. ApoE4 also activated PKC-α and PKB possibly giving the subsequent GSK-3β inhibition. Aβ(1–42) effects were also biphasic with a strong activation dependent partially on extracellular Ca²⁺ followed by an inactivation. Aβ(1–42) induced an early and potent activation of PKC-α and a late decrease of PKB activity. ApoE4 and Aβ(1–42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Aβ(1–42)-induced early activation of GSK-3β could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3β through activation of upstream kinases likely compensates the effects of apoE4 and Aβ(1–42) on GSK-3β, the unbalanced regulation of which may contribute to AD pathology.