Lithium chloride increases the production of amyloid-β peptide independently from its inhibition of glycogen synthase kinase 3

Abstract

Glycogen synthase kinase 3 (GSK3) is able to phosphorylate tau at many sites that are found to be phosphorylated in paired helical filaments in Alzheimer disease. Lithium chloride (LiCl) efficiently inhibits GSK3 and was recently reported to also decrease the production of amyloid-β peptide (Aβ) from its precursor, the amyloid precursor protein. Therefore, lithium has been proposed as a combined therapeutic agent, inhibiting both the hyperphosphorylation of tau and the production of Aβ. Here, we demonstrate that the inhibition of GSK3 by LiCl induced the nuclear translocation of β-catenin in Chinese hamster ovary cells and rat cultured neurons, in which a decrease in tau phosphorylation was observed. In both cellular models, a nontoxic concentration of LiCl increased the production of Aβ by increasing the β-cleavage of amyloid precursor protein, generating more substrate for an unmodified γ-secretase activity. SB415286, another GSK3 inhibitor, induced the nuclear translocation of β-catenin and slightly decreased Aβ production. It is concluded that the LiCl-mediated increase in Aβ production is not related to GSK3 inhibition. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.