Metallostasis and amyloid ?-degrading enzymes

Amyloid-Beta (A?) is a major constituent of senile plaques and one of the principle hallmarks of Alzheimer's disease (AD). The peptide is produced by proteolytic cleavage of the larger amyloid precursor protein (APP). Increased production and aggregation of the peptide are associated with pathology. Emerging evidence suggests that the steady-state levels of A? are determined by the balance between its production and degradation. For this reason, the tuning of the activity of enzymes that degrade A? may be a promising approach in the development of novel therapeutics aimed at reducing A? concentration by enhancing its removal. A great part of A? degrading enzymes are known to be metalloproteases. In the last decade increasing evidence supported the idea that metal ion homeostasis is affected in several regions of AD brain and metals play an important role in tuning enzyme activity. There are three main different pathways by which metal ions can affect the proteolytic enzymes responsible for A? peptides degradation, as metal ions can: (i) form complexes with A? peptides that are not easily degraded; (ii) directly bind to degradative enzymes; (iii) produce signalling cascades that alter enzymes activity involved in A? catabolism. In the current literature the three points mentioned above are very often puzzled, resulting in a quite fragmentary scenario. The aim of this work is to find a link between metal ion homeostasis and A? degradation by separating and analysing the three different pathways proposed. © The 2012 Royal Society of Chemistry.