期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 53, 页码 41443-41454出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.141390
关键词
-
资金
- United Kingdom Medical Research Council [G9824728, G0501565, G0802189]
- Alzheimer's Research Trust [ART/PG2008/2, ART/PhD2009/4]
- MRC [G0501565, G9824728, G0802189] Funding Source: UKRI
- Alzheimers Research UK [ART-PG2008-2, ART-PhD2009-4] Funding Source: researchfish
- Medical Research Council [G0802189, G0501565, G0000701, G9824728] Funding Source: researchfish
Amyloidogenic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases generates several biologically active products, including amyloid-beta (A beta) and the APP intracellular domain (AICD). AICD regulates transcription of several neuronal genes, especially the A beta-degrading enzyme, neprilysin (NEP). APP exists in several alternatively spliced isoforms, APP(695), APP(751), and APP(770). We have examined whether each isoform can contribute to AICD generation and hence up-regulation of NEP expression. Using SH-SY5Y neuronal cells stably expressing each of the APP isoforms, we observed that only APP(695) up-regulated nuclear AICD levels (9-fold) and NEP expression (6-fold). Increased NEP expression was abolished by a beta- or gamma-secretase inhibitor but not an alpha-secretase inhibitor. This correlated with a marked increase in both A beta(1-40) and A beta(1-42) in APP(695) cells as compared with APP(751) or APP(770) cells. Similar phenomena were observed in Neuro2a but not HEK293 cells. SH-SY5Y cells expressing the Swedish mutant of APP(695) also showed an increase in A beta levels and NEP expression as compared with wild-type APP(695) cells. Chromatin immunoprecipitation revealed that AICD was associated with the NEP promoter in APP(695), Neuro2a, and APP(Swe) cells but not APP(751) nor APP(770) cells where AICD was replaced by histone deacetylase 1 (HDAC1). AICD occupancy of the NEP promoter was replaced by HDAC1 after treatment of the APP(695) cells with a beta- but not an alpha-secretase inhibitor. The increased AICD and NEP levels were significantly reduced in cholesterol-depleted APP(695) cells. In conclusion, A beta and functional AICD appear to be preferentially synthesized through beta-secretase action on APP(695).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据