Inhibition of PSecretase

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In sporadic AD patients, BACE-1 enzymatic activity is increased and correlates with the AP peptide load (Fukumoto, Cheung, Hyman, & Irizarry, 2002; Li et al., 2004). Mice deficient in BACE1 are viable and healthy, yet have almost completely abolished production of Ap (Cai et al., 2001; Luo et al., 2001). Targeting BACE-1 with siRNAs ameliorates AD neuropathology in a transgenic model (Singer et al., 2005). Together, these findings indicate that BACE1 is potentially an ideal therapeutic target for blocking Ap production. The crystal structure of BACE-1 has been determined facilitating the rational design of inhibitors (Hong et al., 2000). However, the long substrate-binding site in the enzyme means that compounds that are large enough to ensure good potency are not optimal to allow adequate central nervous system penetration. Despite this, several peptide-based inhibitors have been described (Citron, 2004a, 2004b; Hussain, 2004). Some of these compounds have been shown to inhibit Ap production in vivo in transgenic mice (Asai et al., 2006; Chang et al., 2004). In addition, some BACE-1 inhibitors are reportedly in phase I clinical trials (Pangalos, Jacobsen, & Reinhart, 2005; Vardy, Hussain, & Hooper, 2006).

A number of cellular factors have also been reported to regulate BACE-1 activity. For example, members of the reticulon family of proteins (also known as Nogo proteins) have been shown to bind to BACE-1 and inhibit its activity (He et al., 2004). The leucine zipper protein PAR-4 (prostate apoptosis response-4) has been shown to form a complex with the cytosolic domain of BACE-1, and upon binding increases its activity (Xie & Guo, 2005). The vacuolar protein-sorting protein sorLA interacts with the cytoplasmic domains of both BACE-1 and APP, disrupting BACE-1-APP interactions and reducing the BACE-1 cleavage of APP (Andersen et al., 2005; Spoelgen et al., 2006). Also, the cellular form of the prion protein downregulates the BACE-1 cleavage of APP (Parkin et al., 2007). It remains to be seen whether any of these biological interactions can be exploited to design therapeutics that will inhibit BACE-1 activity. Recently, inhibition of the BACE-1 cleavage of APP with antibodies raised against epitopes adjacent to or at the BACE-1 cleavage site within APP have been described (Arbel, Yacoby, & Solomon, 2005; Paganetti, Calanca, Galli, Stefani, & Molinari, 2005), thus such blocking antibodies may be a further area worthy of therapeutic development.

Lipid rafts, domains of the plasma membrane enriched in cholesterol, glycosphingolipids, sphingomyelin, and glycosyl phosphatidylinositol (GPI)-anchored proteins, have been implicated in a range of biological processes, including intracellular trafficking, transmembrane signaling, lipid and protein sorting, viral uptake, and regulated proteolysis (Brown & London, 1998; Simons & Ehehalt, 2002). Rafts are characterized by their relative insolubility at 4°C in certain detergents such as Triton X-100 (Hooper, 1999). It has been hypothesized that the amyloidogenic processing of APP occurs primarily in rafts, while the nonamyloidogenic processing occurs in nonraft regions of the membrane (Wolozin, 2001). Although only a minor proportion of APP, presenilin, and BACE-1 are localized to rafts (Parkin, Hussain, Karran, Turner, & Hooper, 1999; Parkin, Hussain, Turner, & Hooper, 1997; Riddell, Christie, Hussain, & Dingwall, 2001), experimental evidence does support the occurrence of amyloidogenic processing in these domains (Riddell et al., 2001; Wahrle et al., 2002). Significantly, reduction of cellular cholesterol, which disrupts the structure and function of rafts, results in a decrease in Aß production and an increase in sAPPa formation (Fassbender et al., 2001; Kojro, Gimpl, Lammich, Marz, & Fahrenholz, 2001; Refolo et al., 2001). Such an alteration in the processing of APP may, in part, account for the beneficial effect of cholesterol-lowering drugs, namely statins, in reducing the prevalence of AD (Wolozin, Kellman, Ruosseau, Celesia, & Siegel, 2000). The significance of rafts in APP processing has been investigated using the novel approach of targeting BACE-1 exclusively to rafts by replacing its transmembrane and cytosolic domains with a GPI anchor (Cordy, Hussain, Dingwall, Hooper, & Turner, 2003). Expression of this GPI-anchored form of BACE-1 substantially upregulated the secretion of both sAPPß and Aß over levels observed from cells overexpressing wild-type BACE-1. This effect was reversed when rafts were disrupted by depleting cellular cholesterol. These data indicate that processing of APP to Aß occurs predominantly in rafts and they are in agreement with another report showing that antibody cross-linking induced copatching of APP, BACE-1, and raft marker proteins and increased Aß production (Ehehalt, Keller, Haass, Thiele, & Simons, 2003) (reviewed in Kaether & Haass, 2004; Cordy, Hooper, & Turner, 2006). However, another study reported that the loss of neuronal membrane cholesterol appeared to enhance Aß generation (Abad-Rodriguez et al., 2004). Thus, although modulation of cellular cholesterol levels clearly alters Aß production, the anti-AD effects of the statins may not be due solely to alterations in the processing of APP in lipid rafts but also via other mechanisms, such as their antiinflammatory or antioxidant properties.

A number of other substrates for BACE-1 have been identified, including the APP-like proteins APLP1 and APLP2, ß-galactoside a2,6-sialyltrans-ferase (ST6Gal I), P-selectin glycoprotein ligand-1, low-density lipoprotein receptor-related protein (LRP), and the ß-subunit of voltage-gated sodium channels (von Arnim et al., 2005, Hussain, 2004; Kitazume et al., 2005). As the role of BACE-1 cleavage in the function of these proteins remains unclear, inhibition of BACE-1 in humans might have unexpected and undesirable consequences as a result of the inhibition of the cleavage of one or more of these additional substrates.

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