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, Ca 2+ ‐independent and early activation of GSK‐3β. ApoE4 effects were biphasic, with an early strong GSK‐3β activation that was partially dependent on extracellular Ca 2+ , 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 Ca 2+ 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.