Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid.

Sporadic Alzheimer's disease (AD) is associated with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. The protein levels and activity of the Zn-dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu binding motifs that can prevent this inhibition. Divalent copper noncompetitively inhibited NEP ( K = 1.0 μM),  while proteolysis of Aβ yielded the soluble, Aβ fragment that can bind Cu with femtomolar affinity at pH 7.4. This provides Aβ with the potential to act as a Cu carrier and to mediate its own production by preventing NEP inhibition. Enzyme inhibition at high Zn concentrations ( K = 20 μM) further suggests a mechanism for modulating NEP activity, Aβ production, and Cu homeostasis.