Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer%26apos;s disease?

作者：Nalivaeva Natalia N^*; Beckett Caroline; Belyaev Nikolai D; Turner Anthony J

来源：Journal of Neurochemistry, 2012, 120: 167-185.

DOI：10.1111/j.1471-4159.2011.07510.x

• amyloid ss-peptide
• angiotensin-converting enzyme
• endothelin-converting enzyme
• insulin-degrading enzyme
• neprilysin
• valproate

The amyloid cascade hypothesis of Alzheimers disease envisages that the initial elevation of amyloid beta-peptide (A beta) levels, especially of A beta 1-42, is the primary trigger for the neuronal cell death specific to onset of Alzheimers 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 Alzheimers 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.

• 出版日期2012-1