Protein kinase C inhibits amyloid β-peptide neurotoxicity by acting on members of the Wnt pathway

Current evidence supports the notion that the amyloid beta-peptide (Abeta) plays a major role in the neurotoxicity observed in the brain in Alzheimer's disease. However, the signal transduction mechanisms involved still remain unknown. In the present work, we analyzed the effect of protein kinase C (PKC) on some members of the Writ signaling pathway and its implications for Abeta neurotoxicity. Activation of PKC by phorbol 12-myristate 13-acetate protected rat hippocampal neurons from A(3 toxicity. This effect was accomplished by inhibition of glycogen synthase kinase-3beta (GSK-3beta) activity, which led to the accumulation of cytoplasmic beta-catenin and transcriptional activation via beta-catenin/T-cell factor/lymphoid enhancer factor-1 (TCF/LEF-1) of Writ target genes, which in the present study were engrailed-1 (en-1) and cyclin D1 (cycD1). In contrast, inhibition of Ca2+-dependent PKC isoforms activated GSK-3beta and offered no protection from Abeta neurotoxicity. Wnt-3a and lithium salts, classical activators of the Writ pathway, mimicked PKC activation. Our results suggest that regulation of members of the Writ signaling pathway by Ca2+-dependent PKC isoforms may be important in controlling the neurotoxic process induced by Abeta.