Protein kinase C inhibits amyloid beta 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 Wnt signaling pathway and its implications for Abeta neurotoxicity. Activation of PKC by phorbol 12-myristate 13-acetate protected rat hippocampal neurons from Abeta 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 Wnt 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 Ab neurotoxicity. Wnt-3a and lithium salts, classical activators of the Wnt pathway, mimicked PKC activation. Our results suggest that regulation of members of the Wnt signaling pathway by Ca2+-dependent PKC isoforms may be important in controlling the neurotoxic process induced by Ab.
Garrido
José L
JL
Centro de Regulación Celular y Patología, MIFAB, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago.
Godoy
Juan A
JA
Alvarez
Alejandra
A
Bronfman
Miguel
M
Inestrosa
Nibaldo C
NC
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D051821:Lymphoid Enhancer-Binding Factor 1; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D016229:Amyloid beta-Peptides; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D010446:Peptide Fragments; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C078592:amyloid beta-protein (1-40); D051176:beta Catenin; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3