Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP.
Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate Abeta degradation. Presenilin-deficient cells fail to degrade Abeta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Abeta-degrading enzyme. Neprilysin activity and expression are also lowered by gamma-secretase inhibitors and by PS1/PS2 deficiency in mouse brain. Neprilysin activity is restored by transient expression of PS1 or PS2 and by expression of the amyloid intracellular domain (AICD), which is cogenerated with Abeta, during gamma-secretase cleavage of betaAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Abeta or by the gamma-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Abeta levels with varying levels of gamma-secretase activity.
Pardossi-Piquard
Raphaëlle
R
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR6097 CNRS/UNSA, Valbonne 06560, France.
Petit
Agnès
A
Kawarai
Toshitaka
T
Sunyach
Claire
C
Alves da Costa
Cristine
C
Vincent
Bruno
B
Ring
Sabine
S
D'Adamio
Luciano
L
Shen
Jie
J
Müller
Ulrike
U
St George Hyslop
Peter
P
Checler
Frédéric
F
D000368:Aged; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular / Q000379:methods; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D016296:Mutagenesis / Q000502:physiology; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051880:Receptors, Notch; D011994:Recombinant Proteins; D013997:Time Factors; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D015820:Cadherins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010446:Peptide Fragments; D051880:Receptors, Notch; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D015260:Neprilysin