Choi Doo-Sup, Wang Dan, Yu Gui-Qui, Zhu Guofen, Kharazia Viktor N, Paredes J Peter, Chang Wesley S, Deitchman Jason K, Mucke Lennart, Messing Robert O
Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8215-20. doi: 10.1073/pnas.0509725103. Epub 2006 May 12.
Deposition of plaques containing amyloid beta (Abeta) peptides is a neuropathological hallmark of Alzheimer's disease (AD). Here we demonstrate that neuronal overexpression of the epsilon isozyme of PKC decreases Abeta levels, plaque burden, and plaque-associated neuritic dystrophy and reactive astrocytosis in transgenic mice expressing familial AD-mutant forms of the human amyloid precursor protein (APP). Compared with APP singly transgenic mice, APP/PKCepsilon doubly transgenic mice had decreased Abeta levels but showed no evidence for altered cleavage of APP. Instead, PKCepsilon overexpression selectively increased the activity of endothelin-converting enzyme, which degrades Abeta. The activities of other Abeta-degrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKCepsilon activity can promote Abeta clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.
含有β-淀粉样蛋白（Aβ）肽的斑块沉积是阿尔茨海默病（AD）的神经病理学标志。在此，我们证明蛋白激酶C（PKC）ε同工酶在神经元中的过表达可降低表达家族性AD突变型人淀粉样前体蛋白（APP）的转基因小鼠的Aβ水平、斑块负荷以及与斑块相关的神经突营养不良和反应性星形细胞增生。与单独的APP转基因小鼠相比，APP/PKCε双转基因小鼠的Aβ水平降低，但未显示APP裂解改变的证据。相反，PKCε的过表达选择性地增加了降解Aβ的内皮素转换酶的活性。其他Aβ降解酶，胰岛素降解酶和中性内肽酶的活性未发生变化。这些结果表明，神经元PKCε活性的增加可通过增加内皮素转换酶的活性促进Aβ清除并减少AD神经病理学。
