Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism

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• 作者：Nodi Dehvari ; Ola Isacsson ; Bengt Winblad ; Angel Cedazo-Minguez ; Richard F. Cowburn
• 关键词：Alzheimer's disease ; Presenilin ; Extracellular regulated kinase ; Protein kinase C ; Phospholipase C
• 刊名：Neuroscience Letters
• 出版年：2008
• 期刊代码：52_03043940
• 类别：neu
• 出版时间：2 May 2008
• 卷：436
• 期：1
• 页码：77-80
• 文件大小：399 K

摘要

Presenilin (PS1 and PS2) mutations cause early-onset familial Alzheimer's disease (AD). In addition to affecting β-amyloid precursor protein (APP) processing and Aβ generation, PSs regulate a number of signaling pathways. We previously showed that PSs regulate both phospholipase C (PLC) and protein kinase C (PKC) c="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> and γ activities. We also reported that PS double knockout mouse embryonic fibroblasts (MEFs) have reduced levels of PKCc="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> and enhanced levels of PKCδ. Here, we determined whether the PS modulation of PLC/PKC has consequences for extracellular regulated kinase (Erk) signaling. Erk has been suggested to be important in AD pathology by modulating APP processing and tau phosphorylation. We found that knocking out PS1 or PS2 alone resulted in increased Erk activity and that this effect could be reversed by the PKCc="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> inhibitor Gö6976. We also found that Erk activity following either PLC or PKC stimulation was significantly lower in PS double knockout cells and that treatment with the PKC activator phorbol 12,13-dibutyrate (PdBu) down-regulated total-Erk levels in all cells except PS double knockouts. These results demonstrate that PSs regulate Erk activity through a PKCc="http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> dependent pathway and that disruption of PLC/PKC signaling in the absence of both PS1 and PS2 results in lower downstream activation of Erk.