Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP

Amyloid beta-peptide (A beta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (beta APP). We report that the presenilins (PS1 and PS2) also regulate A beta degradation. Presenilin-deficient cells fail to degrade A beta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key A beta-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 A beta, during gamma-secretase cleavage of PAPP. Neprilysin gene promoters are transactivated by AlCDs from APP-like proteins (APP, APLP1, and APLP2), but not by A beta 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 A beta levels with varying levels of gamma-secretase.