However, recent evidence indicates that ADAM10 is the major α-secretase responsible

for the ectodomain shedding of APP in the mouse brain (Jorissen et al., 2010, Kuhn et al., 2010 and Postina et al., 2004). Nascent Erastin cost ADAM10 is produced as a zymogen and matures into an active protease only after the liberation of its prodomain by furin or proconvertase 7 in the trans-Golgi secretory pathway ( Lammich et al., 1999). After maturation, the majority of the ADAM10 is transported to the plasma membrane, where it acts as a sheddase for cell surface proteins, such as APP. Recent studies have shown that ADAM10 itself is also subject to shedding in cultured cells ( Parkin and Harris, 2009 and Tousseyn et al., 2009). Numerous studies of metalloprotease family proteins suggest that the prodomain

of ADAM10 plays critical roles in the maturation of the enzyme. The primary function of the prodomain is to keep the ADAM10 zymogen in an inactive status via direct interaction with the catalytic site ( Moss et al., 2007), thereby preventing autocatalysis during biosynthesis. Another function of the prodomain is to serve as an intramolecular chaperone, facilitating the proper folding of other domains of the protein ( Cao et al., 2000 and Shinde et al., 1997). While learn more recombinant ADAM10 lacking the prodomain upon initial synthesis is catalytically ADP ribosylation factor inactive, coexpression of the prodomain in trans has been shown to restore the α-secretase activity of the

enzyme ( Anders et al., 2001). In addition to function as a major α-secretase for APP, ADAM10 plays an essential role in embryonic neurogenesis and brain development (Jorissen et al., 2010 and Pan and Rubin, 1997). Both ADAM10 knockout (KO) and conditional KO mice are lethal in early developmental stages (Hartmann et al., 2002 and Jorissen et al., 2010), potentially due to the lack of ectodomain shedding of Notch and its ligands by ADAM10. Recent studies have shown that neurogenesis in adult hippocampus plays an essential role in learning and memory (Zhao et al., 2008). Whether ADAM10 plays a role in adult hippocampal neurogenesis has yet to be addressed. To assess the candidacy of ADAM10 as a LOAD susceptibility gene, we previously genotyped 30 SNPs that span the gene to test for genetic association with AD. These analyses, followed by targeted resequencing of ADAM10, ultimately led to the identification of two nonsynonymous mutations, Q170H and R181G, in seven LOAD families ( Kim et al., 2009). Overexpression of both mutant forms of ADAM10 in cell cultures significantly increased Aβ levels as compared to wild-type (WT) ADAM10 controls ( Kim et al., 2009). Here, we set out to demonstrate the pathogenicity of the two ADAM10 mutations in transgenic mouse models.