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

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
The steady‐state level of amyloid β‐peptide (Aβ) represents a balance between its biosynthesis from the amyloid precursor protein (APP) through the action of the β‐ and γ‐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 Aβ1−40 and Aβ1−42in 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 Aβ degradation may provide a novel approach to the therapy of Alzheimer's disease.