Immunochemical identification from the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimers disease. metabolism (Haass et al. 1993) derived from the amyloid precursor protein (APP) by the successive action of the – and -secretases (see Haass et al. 2011). As is true for MSDC-0160 any other peptide, the production of A is normally counterbalanced by its elimination via any of several processes operating in parallel, including proteolytic degradation, cell-mediated clearance, passive and active transport, and the aggregation and deposition of A into insoluble aggregates. Although the relative importance of these different pathways remains to be established, a growing body of evidence suggests that proteolytic degradation is usually a particularly significant determinant of cerebral A levels and, by extension, Alzheimer disease (AD) pathogenesis. It has long been hypothesized that sporadic forms of AD may be attributable to defective clearance of A (Selkoe 2001; Tanzi et al. 2004). Nevertheless, despite the obvious appeal of this simple idea, it had remained little more than a theoretic possibility. Recently, using newly developed techniques for quantifying the rates of A production MSDC-0160 and clearance within the cerebrospinal fluid (CSF) in humans MSDC-0160 (Bateman et al. 2006), it was confirmed that sporadic AD patients do indeed exhibit significant defects in the clearance of CSF A (Mawuenyega et al. 2010). Although MSDC-0160 these experiments cannot distinguish precisely which clearance mechanisms are impaired in these patients, these findingstogether with the evidence reviewed in this articlelend strong support to the idea that defective A degradation may be operative in AD. Widespread interest in A degradation did not take hold until the turn of the 21st century. A key turning point in the field came with the first study that was explicitly designed to examine A degradation in the living animal (Iwata et al. 2000). In addition to identifying neprilysin (NEP) as one of the principal A-degrading proteases (ADPs), this study highlighted the pathophysiological significance of A degradation to AD pathogenesis generally, thereby igniting interest in this previously underappreciated aspect of A metabolism. A growing list of ADPs have been identified which, by virtue of their diverse features, contribute in unique ways to the overall economy of brain A. CD282 In this article, we provide an overview of the general features of A degradation followed by a brief description of the some of the best characterized ADPs and their diverse properties. We conclude with a discussion of the feasibility of developing therapies targeting A proteolysis. GENERAL FEATURES A Levels Are Potently Regulated by Proteolytic Degradation A is usually degraded by a large set of proteases with diverse characteristics (Table 1). Abundant evidence shows that ADPs, both collectively and in many cases individually, contribute substantially to the determination of cerebral A levels (Eckman and Eckman 2005; Leissring 2008; Leissring and Saido 2007; Turner and Nalivaeva 2007). In an illustrative study, the half-life of A in brain interstitial fluid (ISF) was quantified in APP transgenic mice lacking or expressing MSDC-0160 NEP (Fig. 1A; Farris et al. 2007). This was accomplished by using in vivo microdialysis to quantify interstitial A levels as a function of time before and after pharmacologic blockade of A production (Farris et al. 2007). Genetic deletion of NEP resulted in a doubling of steady-state A levels and, notably, a significant increase in the half-life of ISF A (Fig. 1B). Conversely, transgenic overexpression of NEP in neurons by eightfold in an APP mouse model lowered A levels by around 90% and, notably, prevented the development of any amyloid plaques or downstream cytopathology when examined up to 14 months of age (Fig. 1C; Leissring et.