Reduction of beta-amyloid levels by novel protein kinase C(epsilon) activators.

Abstract

Isoform-specific protein kinase C (PKC) activators may be useful as therapeutic agents for the treatment of Alzheimer disease. Three new epsilon-specific PKC activators, made by cyclopropanation of polyunsaturated fatty acids, have been developed. These activators, AA-CP4, EPA-CP5, and DHA-CP6, activate PKCepsilon in a dose-dependent manner. Unlike PKC activators that bind to the 1,2-diacylglycerol-binding site, such as bryostatin and phorbol esters, which produce prolonged down-regulation, the new activators produced sustained activation of PKC. When applied to cells expressing human APPSwe/PS1delta, which produce large quantities of beta-amyloid peptide (Abeta), DCP-LA and DHA-CP6 reduced the intracellular and secreted levels of Abeta by 60-70%. In contrast to the marked activation of alpha-secretase produced by PKC activators in fibroblasts, the PKC activators produced only a moderate and transient activation of alpha-secretase in neuronal cells. However, they activated endothelin-converting enzyme to 180% of control levels, suggesting that the Abeta-lowering ability of these PKCepsilon activators is caused by increasing the rate of Abeta degradation by endothelin-converting enzyme and not by activating nonamyloidogenic amyloid precursor protein metabolism.

• Authors: Thomas J Nelson, Changhai Cui, Yuan Luo, Daniel L Alkon
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 50 Pg. 34514-21 (Dec 11 2009) ISSN: 1083-351X [Electronic] United States
• PMID: 19850930 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Cyclopropanes
• Enzyme Activators
• Fatty Acids, Unsaturated
• Protein Kinase C-epsilon
• ADAM Proteins
• ADAM17 Protein

Topics

• ADAM Proteins (metabolism)
• ADAM17 Protein
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Cells, Cultured
• Cyclopropanes (chemistry, metabolism, pharmacology, therapeutic use)
• Enzyme Activation
• Enzyme Activators (chemistry, metabolism, pharmacology, therapeutic use)
• Fatty Acids, Unsaturated (chemistry, metabolism, pharmacology, therapeutic use)
• Humans
• Mice
• Molecular Structure
• Neurons (cytology, metabolism)
• Protein Kinase C-epsilon (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley