Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes

被引:160
|
作者
Hebert, Sebastien S.
Serneels, Lutgarde
Tolia, Alexandra
Craessaerts, Katleen
Derks, Carmen
Filippov, Mikhail A.
Mueller, Ulrike
De Strooper, Bart
机构
[1] Flanders Inetruniv Inst Biotechnol VIB4, CME, B-3000 Louvain, Belgium
[2] Katholieke Univ Leuven, B-3000 Louvain, Belgium
[3] Max Planck Inst Brain Res, D-60598 Frankfurt, Germany
[4] Heidelberg Univ, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany
关键词
Alzheimer's disease; amyloid precursor protein; regulated intramembrane proteolysis; secretase;
D O I
10.1038/sj.embor.7400704
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
gamma-Secretase-dependent regulated intramembrane proteolysis of amyloid precursor protein (APP) releases the APP intracellular domain ( AICD). The question of whether this domain, like the Notch intracellular domain, is involved in nuclear signalling is highly controversial. Although some reports suggest that AICD regulates the expression of KAI1, glycogen synthase kinase-3 beta, Neprilysin and APP, we found no consistent effects of gamma-secretase inhibitors or of genetic deficiencies in the gamma-secretase complex or the APP family on the expression levels of these genes in cells and tissues. Finally, we demonstrate that Fe65, an important AICD-binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression. Overall, the four currently proposed target genes are at best indirectly and weakly influenced by APP processing. Therefore, inhibition of APP processing to decrease A beta generation in Alzheimer's disease will not interfere significantly with the function of these genes.
引用
收藏
页码:739 / 745
页数:7
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