Neprilysin activity and expression are controlled by nicastrin.
We recently demonstrated that the presenilin-dependent gamma-secretase complex regulates the expression and activity of neprilysin, one of the main enzymes that degrade the amyloid beta-peptide (Abeta) which accumulates in Alzheimer's disease. Here, we examined the influence of endogenous nicastrin (NCT), a member of the gamma-secretase complex, on neprilysin physiology. We show that nicastrin deficiency drastically lowers neprilysin expression, membrane-bound activity and mRNA levels, but it did not modulate the expression of two other putative Abeta-cleaving enzymes, endothelin-converting enzyme and insulin-degrading enzyme. Furthermore, we show that nicastrin restores neprilysin activity and expression in nicastrin-deficient, but not presenilin-deficient fibroblasts, indicating that the control of neprilysin necessitates the complete gamma-secretase complex harbouring its four reported components. Finally, we show that NCT expression peaked 24 h after NCT cDNA transfection of wild-type and NCT-/- fibroblasts, while neprilysin expression drastically increased only after 36 h and was maximal at 48 h. This delayed effect on neprilysin expression correlates well with our demonstration of an indirect gamma-secretase-dependent modulation of neprilysin at its transcriptional level.
Pardossi-Piquard
R
R
Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Equipe labellisée Fondation pour la Recherche Médicale, Valbonne, France.
Dunys
J
J
Yu
G
G
St George-Hyslop
P
P
Alves da Costa
C
C
Checler
F
F
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053764:Presenilin-1; D012333:RNA, Messenger; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D015260:Neprilysin