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 Zn²⁺-dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu²⁺ ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu²⁺ binding motifs that can prevent this inhibition. Divalent copper noncompetitively inhibited NEP ( K_i = 1.0 μM),  while proteolysis of Aβ yielded the soluble, Aβ_4-9 fragment that can bind Cu²⁺ with femtomolar affinity at pH 7.4. This provides Aβ_4-9 with the potential to act as a Cu²⁺ carrier and to mediate its own production by preventing NEP inhibition. Enzyme inhibition at high Zn²⁺ concentrations ( K_i = 20 μM) further suggests a mechanism for modulating NEP activity, Aβ_4-9 production, and Cu²⁺ homeostasis.