Neprilysin activity and expression are controlled by nicastrin.

Abstract:

: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.

journal_name

J Neurochem

authors

Pardossi-Piquard R,Dunys J,Yu G,St George-Hyslop P,Alves da Costa C,Checler F

doi

10.1111/j.1471-4159.2006.03822.x

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

1052-6

issue

4

eissn

0022-3042

issn

1471-4159

pii

JNC3822

journal_volume

97

pub_type

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