Inhibition of YSecretase

Y-Secretase is a complex consisting of the presenilins, nicastrin and anterior pharynx defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2), with the presenilins constituting the catalytic site of the complex (Haass, 2004). Presenilin-1 and presenilin-2 are encoded by different genes, mutations of which are inherited in an autosomal dominant fashion causing a particularly aggressive early-onset form of familial AD. Y-Secretase is involved in the intramembrane proteolysis of a number of other substrates in addition to APP, including P-subunits of voltage-gated sodium channels, the immunoglobulin superfamily recognition molecule L1, vascular endothelial growth factor receptor 1, growth hormone receptor, apoER2 lipoprotein receptor, LRP, Erb B4 receptor, CD44, p75 neurotrophin receptor, Nectin-1a, syndecan-3, E- and N-cadherins, and Notch (Cai, Jiang, Grant, & Boulton, 2006; Cowan et al., 2005; Kim, Ingano, Carey, Pettingell, & Kovacs, 2005; Maretzky et al., 2005; Wong et al., 2005). The most widely studied of these other substrates is the transmembrane protein Notch, which is involved in both cellular signaling and cell development (Artavanis-Tsakonas, Matsuno, & Fortini, 1995). Knockout mice without presenilin-1 die soon after birth and exhibit abnormalities of skeletal and neurological development, similar to the phenotype in Notch 1 knockout mice (Struhl & Greenwald, 1999; Zhang et al., 2000).

Although Y-secretase inhibitors have been readily identified from cell-based screens, the finding that this protease mediates the intramembrane proteolysis of a large number of unrelated proteins has raised concern of potential toxic effects, owing to inhibition of the Y-secretase processing of other substrates. However, Lilly have recently reported preliminary safety and tolerability data together with changes in Ap levels for a Y-secretase inhibitor, LY450139 (Siemers et al., 2005), which has now entered a phase II clinical trial. Various other compounds have been identified that also inhibit or modulate Y-secretase activity, including nonpeptidic isocoumarin compounds (JLK inhibitors), STI571 (Gleevec), and nonsteroidal antiinflammatory drugs (NSAIDs) (Beher et al., 2004; Netzer et al., 2003; Petit et al., 2001). Some of these compounds appear to modulate the Y-secretase processing of APP without altering Notch cleavage, raising the possibility of therapeutics that selectively target APP processing.

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