Amyloid-Degrading Enzymes as Therapeutic Targets in Alzheimers Disease

Natalia   N.   Nalivaeva; Lilia   R.   Fisk; Nikolai   D.   Belyaev; Anthony   J.   Turner

Abstract

The steady state concentration of the Alzheimers amyloid-β peptide in the brain represents a balance between its biosynthesis from the transmembrane amyloid precursor protein (APP), its oligomerisation into neurotoxic and stable species and its degradation by a variety of amyloid-degrading enzymes, principally metallopeptidases. These include, among others, neprilysin (NEP) and its homologue endothelin-converting enzyme (ECE), insulysin (IDE), angiotensinconverting enzyme (ACE) and matrix metalloproteinase-9 (MMP-9). In addition, the serine proteinase, plasmin, may participate in extracellular metabolism of the amyloid peptide under regulation of the plasminogen-activator inhibitor. These various amyloid-degrading enzymes have distinct subcellular localizations, and differential responses to aging, oxidative stress and pharmacological agents and their upregulation may provide a novel and viable therapeutic strategy for prevention and treatment of Alzheimers disease. Potential approaches to manipulate expression levels of the key amyloiddegrading enzymes are highlighted.

Keywords: Alzheimer's disease, amyloid β-peptide, amyloid precursor protein, angiotensin-converting enzyme, endothelinconverting enzyme, insulysin, neprilysin, matrix metalloproteinase, plasmin, protease