Reduction of β-Amyloid Levels by Novel Protein Kinase Cε Activators
Reduction of β-Amyloid Levels by Novel Protein Kinase Cε Activators
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DOI：
10.1074/jbc.m109.016683
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Alkon, Daniel L.
中科院分区：
文献类型：
--
作者：
Nelson, Thomas J.;Cui, Changhai;Alkon, Daniel L.
异构体特异性蛋白激酶C （PKC）激活剂可能是治疗阿尔茨海默病的有效药物。以多不饱和脂肪酸为原料，制备了3种新的epsiln特异性PKC激活剂。这些激活剂AA-CP4、EPA-CP5和DHA-CP6以剂量依赖的方式激活PKC epsilon。与结合1,2-二酰基甘油结合位点的PKC激活剂（如苔藓抑素和佛波酯）产生长时间的下调不同，新的激活剂产生PKC的持续激活。当应用于表达人APPSwe/PS1 δ的细胞时，DCP-LA和DHA-CP6使细胞内和分泌的A β水平降低了60-70%。与PKC激活剂在成纤维细胞中产生的α -分泌酶的显著激活相反，PKC激活剂在神经元细胞中仅产生中度和短暂的α -分泌酶激活。然而，他们将内皮素转换酶激活到对照水平的180%，这表明这些PKC epsilon激活剂的A - β降低能力是通过增加内皮素转换酶对A - β的降解速率引起的，而不是通过激活非淀粉样蛋白前体蛋白代谢引起的。
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 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 down-regulation, the new activators produced sustained activation of PKC. When applied to cells expressing human APPSwe/PS1 delta, which produce large quantities of beta-amyloid peptide (A beta), DCP-LA and DHA-CP6 reduced the intracellular and secreted levels of A beta 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 A beta-lowering ability of these PKC epsilon activators is caused by increasing the rate of A beta degradation by endothelin-converting enzyme and not by activating nonamyloidogenic amyloid precursor protein metabolism.