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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