Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease.
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.
Nalivaeva
Natalia N
NN
Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Fisk
Lilia R
LR
Belyaev
Nikolai D
ND
Turner
Anthony J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism
D000682:Amyloid; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D007703:Peptidyl-Dipeptidase A; D005341:Fibrinolysin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D020780:Matrix Metalloproteinase 9; D007339:Insulysin; D000072396:Endothelin-Converting Enzymes