br GSMs Secretase cleavage of

GSMs γ-Secretase cleavage of APP generates a number of Aβ peptides [32], [137]. In most cells Aβ1–37, 38, 39, and 42 are produced at low levels (typically each represents 5–20% of total Aβ detected) and the major species generated is Aβ1–40 (typically over 50% of total Aβ). Other Aβ peptides can also be variably detected at low levels including Aβ1–34, 1–36, 1–41 and 1–43. Shifts in the relative production of these various Aβ peptides towards Aβ1–42, is tightly associated with risk for AD [138], [139]. Mutations in APP and PSEN1/2 that elevate the relative level of Aβ42 by even as little as 30% deterministically cause early onset AD [140], and it now appears that the deposition process likely begins 20years before the onset of dementia in these individuals [141]. Seminal biochemical studies show that Aβ1–42 glutathione reductase into amyloid fibrils and other assemblies much more readily than Aβ1–40 [142], [143], and transgenic modeling studies show that AD-associated APP and PSEN mutations increases Aβ42 levels and accelerate Aβ deposition [144], [145]. In addition other studies using various fusion protein strategies to express Aβ1–42 and Aβ1–40 in the absence of APP overexpression show that Aβ42 is required to drive Aβ deposition, and that Aβ1–40 may actually inhibit Aβ deposition [146], [147], [148], [149]. Some early studies of peptidic GSIs showed that although they reduced total Aβ levels and increased APP CTF; they also shifted the profile of Aβ species produced, in some cases increasing the absolute level of longer Aβ1–41,42, and 43 [30], [32], [33]. As discussed earlier these data fueled some speculation that multiple proteases contributed to the generation of the various Aβ peptides. Subsequently, we identified a subset of non-steroidal anti-inflammatory agents (NSAIDs) such as ibuprofen, sulindac and indomethacin, as prototypic agents capable of lowering Aβ42 selectively in vitro and in vivo by targeting the γ-secretase complex [150], [151], [152]. The classic signature of these first generation GSMs differed from previous GSIs in that they did not alter total Aβ production, or increase APP CTFs and no alterations in the generation of several other γ-secretase substrates, but instead decreased Aβ1–42 levels and increased Aβ1–38 [152]. These data suggested that it may be possible to use GSMs as therapeutic agents for AD as they would selectively target the longer more pathogenic forms of Aβ. In addition to these classic GSMs, other compounds referred to as inverse GSMs (iGSMs) were also identified [153], [154]. These compounds were often structurally related to the GSMs but typically lacked an acidic group, and increased, rather than lowering, Aβ1–42. In some, but not all cases, these compounds also decreased levels of shorter Aβ peptides including (Aβ1–37, 38, 39). Since the initial identification of NSAID-based GSMs there has been a major effort to improve potency, pharmacokinetic properties and find new non-acidic classes of GSMs. This has led to the identification of a number of acidic GMSs with dramatic increases in potency and brain penetrance, and non-acidic GSMs based around a common scaffold that are also much more potent than the first generation NSAID-based GSMs (Fig. 3) [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172]. More recently triterpenoid natural product derived GSMs have been identified [173], [174]. Overall there are subtle differences between these GSMs that may be therapeutically important. While the more potent acidic GSMs show the classic GSM signature of lowering Aβ1–42 and increasing Aβ1–38 [175], non-acidic GSMs increase Aβ1–37 and 1–38 and lower both Aβ1–40 and 1–42 [171]. In contrast, the triterpenoid GSM appears to be even more distinct lowering both Aβ1–38 and 1–42 [173], [174]. These differential properties and comparison to GSIs are described in Table 2.