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Keywords:

  • amyloid;
  • endopeptidase;
  • insulysin;
  • neprilysin;
  • neurodegeneration;
  • neuroprotection

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.