Effect of amyloid-β (Aβ) immunization on hyperphosphorylated tau: A potential role for glycogen synthase kinase (GSK)-3β

Abstract

Aims: Active amyloid-β (Aβ) immunotherapy in Alzheimer's disease (AD) induces removal of Aβ and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aβ immunization on GSK-3β expression and pPKR. Methods: We immunostained 11 immunized AD cases and 28 unimmunized AD cases for active, inactive and total GSK-3β, and for pPKR. Quantification of protein load was performed in the hippocampal region including CA1, subiculum and entorhinal cortex. Results: All three areas showed a significant decrease in the three forms of GSK-3β (P<0.05) and a nonsignificant trend towards lower pPKR load in the immunized AD cases compared with the unimmunized AD cases. Conclusion: The lower GSK-3β expression generated by Aβ immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3β leading to the overall reduction of tau, supporting the contention that in humans, GSK-3β unifies Aβ and tau-related neuropathology.