Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease

作者：Nalivaeva Natalia N; Fisk Lilia R; Belyaev Nikolai D; Turner Anthony J^*

来源：Current Alzheimer Research, 2008, 5(2): 212-224.

DOI：10.2174/156720508783954785

• Alzheimer's disease
• amyloid peptide
• amyloid precursor protein
• angiotensin-converting enzyme
• endothelin-converting enzyme
• insulysin
• neprilysin
• matrix metalloproteinase
• plasmin
• protease

The steady state concentration of the Alzheimer's amyloid-beta 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), angiotensin-converting 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 Alzheimer's disease. Potential approaches to manipulate expression levels of the key amyloid-degrading enzymes are highlighted.

• 出版日期2008-4