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Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes
Author(s) -
Hébert Sébastien S,
Serneels Lutgarde,
Tolia Alexandra,
Craessaerts Katleen,
Derks Carmen,
Filippov Mikhail A,
Müller Ulrike,
De Strooper Bart
Publication year - 2006
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400704
Subject(s) - amyloid precursor protein , biology , gene , amyloid precursor protein secretase , proteolysis , intracellular , neprilysin , microbiology and biotechnology , genetics , biochemistry , alzheimer's disease , enzyme , disease , medicine , pathology
γ‐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‐3β, Neprilysin and APP, we found no consistent effects of γ‐secretase inhibitors or of genetic deficiencies in the γ‐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 Aβ generation in Alzheimer's disease will not interfere significantly with the function of these genes.