Abstract
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of beta-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Animals
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Behavior, Animal / drug effects
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Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism*
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Cell Line
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Computational Biology
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Disease Models, Animal
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Enhancer Elements, Genetic / genetics
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Gene Expression / drug effects
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Gene Expression / genetics
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / pathology
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Humans
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Lithium Chloride / pharmacology
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Lithium Chloride / therapeutic use
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Neurons / drug effects
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Neurons / metabolism
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Neuropsychological Tests
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Promoter Regions, Genetic / genetics
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Protein Binding / genetics
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Rats
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Rats, Inbred Strains
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Signal Transduction / physiology*
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TCF Transcription Factors / metabolism
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Transfection
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Wnt Proteins / metabolism*
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Wnt Proteins / pharmacology
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Wnt3 Protein
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Wnt3A Protein
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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TCF Transcription Factors
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WNT3A protein, human
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Wnt Proteins
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Wnt3 Protein
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Wnt3A Protein
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Wnt3a protein, mouse
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beta Catenin
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Lithium Chloride