β‐Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases?

Abstract

The steady-state level of amyloid b-peptide (Ab) represents a balance between its biosynthesis from the amyloid precursor protein (APP) through the action of the b-and c-secretases and its catabolism by a variety of proteolytic enzymes. Recent attention has focused on members of the neprilysin (NEP) family of zinc metalloproteinases in amyloid metabolism. NEP itself degrades both Ab 1)40 and Ab 1)42 in vitro and in vivo, and this metabolism is prevented by NEP inhibitors. Other NEP family members, for example endothelin-converting enzyme, may contribute to amyloid catabolism and may also play a role in neuroprotection. Another metalloproteinase, insulysin (insulin-degrading enzyme) has also been advocated as an amyloid-degrading enzyme and may contribute more generally to metabolism of amyloid-forming peptides. Other candidate enzymes proposed include angiotensin-converting enzyme, some matrix metalloproteinases, plasmin and, indirectly, thimet oligopeptidase (endopeptidase-24.15). This review critically evaluates the evidence relating to proteinases implicated in amyloid catabolism. Therapeutic strategies aimed at promoting Ab degradation may provide a novel approach to the therapy of Alzheimer's disease.

Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

“…Because PAO accumulation is directly correlated with the severity of cardiac disease (15), we examined the potential causes for its accumulation. Recent data indicate that amyloid-rich neural samples from patients with neurodegenerative disease show significantly reduced levels of the metallomembrane endopeptidase neprilysin (23)(24)(25). The formation of amyloid and preamyloid depositions can be enzymatically regulated by this enzyme (23), and we hypothesized that PAO accumulation in the hearts of CryAB R120G mice might be partially dependent on diminished neprilysin activity.…”

Prion protein and Alzheimer disease

“…In normal brains, Aβ is degraded by multiple peptidases, including neprilysin, endothelin-converting enzyme and insulin-degrading enzyme. 21 While Aβ is commonly thought of as the main toxic agent in AD, there is emerging evidence of a normal physiological role for the peptide in the regulation of neuronal calcium and potassium channel currents. 22,23 This, therefore, indicates that Aβ should only be considered as a toxic agent when levels increase as a result of an imbalance in its production and degradation/ clearance, such as occurs in AD.…”

Functional characterization of the Mycobacterium tuberculosis zinc metallopeptidase Zmp1 and identification of potential substrates

“…The targets of M13 members usually are bioactive peptides with a key function in the regulation of cardiovascular, nervous, and immune systems (Turner et al , 2001 ). Zmp1 shares particularly primary sequence similarity (48 % ) with human neprilysin (NEP; 749 aa), an extracellular peptidase that preferentially hydrolyzes extracellular oligopeptides ( < 5 kDa) on the amino side of hydrophobic residues (also including amyloid β peptides implicated in Alzheimer disease) (Carson and Turner , 2002 ;Madani et al , 2006 ). We recently solved the crystal structure of Zmp1, and our investigation demonstrated that Zmp1 and NEP are also structurally conserved (Ferraris et al , 2011 ).…”