Notch1 competes with the amyloid precursor protein for gamma-secretase and down-regulates presenilin-1 gene expression.
Presenilin 1 (PS1) is a critical component of the gamma-secretase complex, which is involved in the cleavage of several substrates including the amyloid precursor protein (APP) and Notch1. Based on the fact that APP and Notch are processed by the same gamma-secretase, we postulated that APP and Notch compete for the enzyme activity. In this report, we examined the interactions between APP, Notch, and PS1 using the direct gamma-secretase substrates, Notch 1 Delta extracellular domain (N1DeltaEC) and APP carboxyl-terminal fragment of 99 amino acids, and measured the effects on amyloid-beta protein production and Notch signaling, respectively. Additionally, we tested the hypothesis that downstream effects on PS1 expression may coexist with the competition phenomenon. We observed significant competition between Notch and APP for gamma-secretase activity; transfection with either of two direct substrates of gamma-secretase led to a reduction in the gamma-cleaved products, Notch intracellular domain or amyloid-beta protein. In addition, however, we found that activation of the Notch signaling pathway, by either N1 Delta EC or Notch intracellular domain, induced down-regulation of PS1 gene expression. This finding suggests that Notch activation directly engages gamma-secretase and subsequently leads to diminished PS1 expression, suggesting a complex set of feedback interactions following Notch activation.
Lleó
Alberto
A
Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02114, USA.
Berezovska
Oksana
O
Ramdya
Pavan
P
Fukumoto
Hiroaki
H
Raju
Susan
S
Shah
Tejal
T
Hyman
Bradley T
BT
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001667:Binding, Competitive; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D010450:Endopeptidases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D053764:Presenilin-1; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D008156:Luciferases; D001616:beta-Galactosidase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse