Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease?
Article first published online: 28 NOV 2011
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Special Issue: Alzheimer’s Disease
Volume 120, Issue Supplement s1, pages 167–185, January 2012
How to Cite
Nalivaeva, N. N., Beckett, C., Belyaev, N. D. and Turner, A. J. (2012), Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease?. Journal of Neurochemistry, 120: 167–185. doi: 10.1111/j.1471-4159.2011.07510.x
- Issue published online: 23 DEC 2011
- Article first published online: 28 NOV 2011
- Received August 10, 2011; revised manuscript received September 23, 2011; accepted September 27, 2011.
- amyloid β-peptide;
- angiotensin-converting enzyme;
- endothelin-converting enzyme;
- insulin-degrading enzyme;
J. Neurochem. (2012) 120 (Suppl. 1), 167–185.
The amyloid cascade hypothesis of Alzheimer’s disease envisages that the initial elevation of amyloid β-peptide (Aβ) levels, especially of Aβ1-42, is the primary trigger for the neuronal cell death specific to onset of Alzheimer’s disease. There is now substantial evidence that brain amyloid levels are manipulable because of a dynamic equilibrium between their synthesis from the amyloid precursor protein and their removal by amyloid-degrading enzymes (ADEs) providing a potential therapeutic strategy. Since the initial reports over a decade ago that two zinc metallopeptidases, insulin-degrading enzyme and neprilysin (NEP), contributed to amyloid degradation in the brain, there is now an embarras de richesses in relation to this category of enzymes, which currently number almost 20. These now include serine and cysteine proteinases, as well as numerous zinc peptidases. The experimental validation for each of these enzymes, and which to target, varies enormously but up-regulation of several of them individually in mouse models of Alzheimer’s disease has proved effective in amyloid and plaque clearance, as well as cognitive enhancement. The relative status of each of these enzymes will be critically evaluated. NEP and its homologues, as well as insulin-degrading enzyme, remain as principal ADEs and recently discovered mechanisms of epigenetic regulation of NEP expression potentially open new avenues in manipulation of AD-related genes, including ADEs.