TY - JOUR
T1 - Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP
AU - Pardossi-Piquard, Raphaëlle
AU - Petit, Agnès
AU - Kawarai, Toshitaka
AU - Sunyach, Claire
AU - Da Costa, Cristine Alves
AU - Vincent, Bruno
AU - Ring, Sabine
AU - D'Adamio, Luciano
AU - Shen, Jie
AU - Müller, Ulrike
AU - Hyslop, Peter St George
AU - Checler, Frédéric
N1 - Funding Information:
We sincerely thank Drs. B. De Strooper, P. Saftig, F. Chen, Q. Hu, G. Martin, C. Dumanchin, D. Campion, N. Girardot, and C. Duyckaerts for providing cell lines and brain tissues. We are grateful to Drs. T.C. Sudhof, R. Kopan, P. Marambaud, J.P. Borg, F. Authier, G. Boileau, L. Mercken, and W. Araki for generously providing us with cDNAs and antibodies. This work was supported by the EU contract LSHM-CT-2003-503330 (APOPIS), by the Association France Alzheimer (RPP) and by the Fondation pour la Recherche Médicale (C.S.). Drs. P. St. George-Hyslop and Toshitaka Kawarai are supported by the Canadian Institutes of Health Research, Howard Hughes Medical Institute, and Alzheimer Society of Ontario. This work is dedicated to our friend and colleague Nicole Boyer, who died suddenly on April 19, 2005.
PY - 2005/5/19
Y1 - 2005/5/19
N2 - Amyloid β-peptide (Aβ), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent γ-secretase cleavage of β-amyloid precursor protein (βAPP). We report that the presenilins (PS1 and PS2) also regulate Aβ degradation. Presenilin-deficient cells fail to degrade Aβ and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Aβ-degrading enzyme. Neprilysin activity and expression are also lowered by γ-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 Aβ, during γ-secretase cleavage of βAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Aβ or by the γ-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Aβ levels with varying levels of γ-secretase activity.
AB - Amyloid β-peptide (Aβ), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent γ-secretase cleavage of β-amyloid precursor protein (βAPP). We report that the presenilins (PS1 and PS2) also regulate Aβ degradation. Presenilin-deficient cells fail to degrade Aβ and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Aβ-degrading enzyme. Neprilysin activity and expression are also lowered by γ-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 Aβ, during γ-secretase cleavage of βAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Aβ or by the γ-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Aβ levels with varying levels of γ-secretase activity.
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U2 - 10.1016/j.neuron.2005.04.008
DO - 10.1016/j.neuron.2005.04.008
M3 - Article
C2 - 15944124
AN - SCOPUS:20444398562
SN - 0896-6273
VL - 46
SP - 541
EP - 554
JO - Neuron
JF - Neuron
IS - 4
ER -