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Protein kinase C inhibits amyloid β‐peptide neurotoxicity by acting on members of the Wnt pathway
Author(s) -
Garrido José L.,
Godoy Juan,
Alvarez Alejandra,
Bronfman Miguel,
Inestrosa Nibaldo C.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0327fje
Subject(s) - wnt signaling pathway , protein kinase c , gsk 3 , neurotoxicity , signal transduction , microbiology and biotechnology , chemistry , fyn , biology , gsk3b , proto oncogene tyrosine protein kinase src , toxicity , organic chemistry
ABSTRACT Current evidence supports the notion that the amyloid β‐peptide (Aβ) 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 Aβ neurotoxicity. Activation of PKC by phorbol 12‐myristate 13‐acetate protected rat hippocampal neurons from Aβ toxicity. This effect was accomplished by inhibition of glycogen synthase kinase‐3β (GSK‐3β) activity, which led to the accumulation of cytoplasmic β‐catenin and transcriptional activation via β‐catenin/T‐cell factor/lymphoid enhancer factor‐1 (TCF/LEF1) of Wnt target genes, which in the present study were engrailed‐1 (en‐1) and cyclin D1 (cycD1). In contrast, inhibition of Ca 2+ ‐dependent PKC isoforms activated GSK‐3β and offered no protection from Aβ 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 Ca 2+ ‐dependent PKC isoforms may be important in controlling the neurotoxic process induced by Aβ.