Reduction of beta-amyloid levels by novel protein kinase C(epsilon) activators.
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.
Nelson
Thomas J
TJ
Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia 26506, USA. tjnelson@brneurosci.org
Cui
Changhai
C
Luo
Yuan
Y
Alkon
Daniel L
DL
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D003521:Cyclopropanes; D020536:Enzyme Activators; D005231:Fatty Acids, Unsaturated; D051744:Protein Kinase C-epsilon; D051722:ADAM Proteins; D000072198:ADAM17 Protein