In the nonamyloidogenic pathway, APP is cleaved within the Ap domain by a-secretase (Fig. 1). This proteolytic cleavage prevents the deposition of intact Ap peptide and results in the release of a large soluble ectodomain, sAPPa from the cell that has neuroprotective and memory-enhancing effects (Barger & Harmon, 1997; Meziane et al., 1998). Under normal circumstances, the majority of APP is cleaved by a-secretase, with minimal processing by P-secretase. As the a- and P-secretases compete for the same substrate, an increase in AP production correlates with a decrease in sAPPa levels and vice versa (Caporaso, Gandy, Buxbaum, Ramabhadran, & Greengard, 1992; Hung et al., 1993; Savage et al., 1998). Consistent with this, AD patients have decreased levels of sAPPa in their cerebrospinal fluid (Lannfelt, Basun, Wahlund, Rowe, & Wagner, 1995; Van Nostrand et al., 1992). Members of the ADAM family of proteases, namely ADAM-9, ADAM-10, and tumor necrosis factor-a convertase (TACE, ADAM-17), have been shown to possess a-secretase activity (reviewed in Allinson et al., 2003; Hooper & Turner, 2002). A consensus view appears to be emerging that there is a team of metalloproteases able to cleave APP at the a-secretase site. In different cell types, and possibly under particular cellular conditions, different members of this team contribute to a greater or lesser extent to the a-secretase cleavage of APP. For example, in the human neuroblastoma SH-SY5Y cell line, it has been shown, using selective inhibitors (Parkin et al., 2002; Parvathy, Karran, Turner, & Hooper, 1998) and an antisense-oligonucleotide approach (Allinson et al., 2004), that ADAM-10 has a major role in the constitutive cleavage of APP with ADAM-17 having a minor role. However, ADAM-17 may have a more significant role to play in the protein kinase C-stimulated cleavage of APP (Buxbaum et al., 1998).
That upregulation of a-secretase activity would preclude the formation of AP has recently been demonstrated in transgenic mice with moderate neuronal overexpression of ADAM-10 (Postina et al., 2004). In these mice there was increased secretion of sAPPa, reduced AP production, delayed plaque formation, and alleviation of cognitive deficits. A variety of agents have been shown to increase a-secretase activity in cell and animal models, including muscarinic agonists, protein kinase C activators, serotonin, glutamate, estrogen, testosterone, cholesterol-lowering drugs, and pituitary adenylate cyclase-activating polypeptide (PACAP) (Kojro et al., 2006; Vardy et al., 2005). Although some of these agents have been subject to clinical trial, there is as yet no evidence to support the routine use of any of them in the treatment of AD. Recently, it has been shown that the acetylcholinesterase inhibitors may exhibit some of their effects through stimulating the nonamyloidogenic a-secretase cleavage of APP (Francis, Nordberg, & Arnold, 2005; Zimmermann et al., 2004). Thus, although activation of a-secretase is not conceptually as simple as inhibition of P- and y-secretase (Fig. 2), the possibility of drugs with increased selectivity towards activating a-secretase might hold promise as AD therapeutics in the future.
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