Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes.
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-3beta, 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 Abeta generation in Alzheimer's disease will not interfere significantly with the function of these genes.
Hébert
Sébastien S
SS
Neuronal Cell Biology and Gene Transfer, CME, Flanders Interuniversity Institute for Biotechnolog, VIB4, and Katholieke Universiteit Leuven, Herestraat 49, Leuven 3000, Belgium.
Serneels
Lutgarde
L
Tolia
Alexandra
A
Craessaerts
Katleen
K
Derks
Carmen
C
Filippov
Mikhail A
MA
Müller
Ulrike
U
De Strooper
Bart
B
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008566:Membranes / Q000378:metabolism; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse