Reduction of beta-amyloid levels by novel PKCepsilon activators

Abstract Isoform-specific protein kinase C (PKC) activators may be useful as therapeutic agents for the treatment of Alzheimer's 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 PKC epsilon 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 downregulation, the new activators produced sustained activation of PKC. When applied to cells expressing human APPSwe/PS1Delta, which produce large quantities of 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 (ECE) to 180% of control levels, suggesting that the Abeta-lowering ability of these PKC epsilon activators is caused by increasing the rate of Abeta degradation by ECE, and not by activating nonamyloidogenic APP metabolism.