A Distinct ER/IC -Secretase Competes with the Proteasome for Cleavage of APP

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• 作者：Daniel M. Skovronsky ; Donald S. Pijak ; Robert W. Doms ; and Virginia M.-Y. Lee
• 刊名：Biochemistry
• 出版年：2000
• 出版时间：February 1, 2000
• 年：2000
• 卷：39
• 期：4
• 页码：810 - 817
• 全文大小：211K
• 年卷期：v.39,no.4(February 1, 2000)
• ISSN：1520-4995

文摘

The deposition of amyloid-mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> peptides (Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">) in senile plaques (SPs) is a central pathologicalfeature of Alzheimer's disease (AD). Since SPs are composed predominantly of Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42, which is moreamyloidogenic in vitro, the enzymes involved in generating Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 may be particularly important tothe pathogenesis of AD. In contrast to Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-40, which is generated in the trans-Golgi network and othercytoplasmic organelles, intracellular Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 is produced in the endoplasmic reticulum/intermediatecompartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production ofintracellular Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> is regulated. Surprisingly, the production of insoluble intracellular Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 was increasedby a putative mages/gifchars/gamma.gif" BORDER=0 >-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstratethat this increased generation of Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 in the ER/IC is due to a reduction in the turnover of Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation ofER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminalfragments for mages/gifchars/gamma.gif" BORDER=0 >-secretase cleavage and thereby increase production of Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 in the ER/IC. Based onthe organelle-specific differences in the generation of Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> by mages/gifchars/gamma.gif" BORDER=0 >-secretase, we conclude that intracellularER/IC-generated Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42 and secreted Amages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-40 are produced by different mages/gifchars/gamma.gif" BORDER=0 >-secretases. Further, the factthat a putative mages/gifchars/gamma.gif" BORDER=0 >-secretase inhibitor had opposite effects on the production of secreted and intracellularAmages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> may have important implications for AD drug design.