ADAM10 is a type I membrane protein synthesized as an inactive proenzyme and has an N-terminal prodomain that is removed by furin or proprotein convertase 7 (PC7) in the trans-Golgi network in order for the protease to become active ( Figure 1B). GSK3 inhibitor Mature ADAM10 resides on the cell surface, where it performs ectodomain shedding of diverse membrane protein substrates, including APP. Although a major function of the ADAM10 prodomain is to maintain the enzyme in an inactive state during synthesis and maturation, the prodomain also functions as an intramolecular chaperone that assists in the correct folding of the enzyme’s various domains. The importance

of prodomain chaperone function is underscored by the observation that expression of a prodomain-deleted ADAM10 construct results in a proteolytically inactive enzyme, whereas coexpression in trans of the prodomain with prodomain-deleted ADAM10 rescues enzyme activity ( Anders et al., 2001). Given the role of ADAM10 as the major APP α-secretase in the brain, Rudy Tanzi and colleagues at Massachusetts General Hospital and Harvard University assessed the candidacy of ADAM10 as a LOAD susceptibility gene. In a previous

study, the group genotyped 30 SNPs that spanned ADAM10 and then performed targeted resequencing of the gene. This investigation identified two rare highly penetrant nonsynonymous mutations (Q170H and R181G) associated with LOAD in the prodomain of ADAM10 ( Kim et al., 2009). These mutations occurred in 11 of 16 Panobinostat affected individuals from seven LOAD-affected families. In cell-culture experiments, ADAM10 with either the Q170H or the R181G prodomain mutation exhibited α-secretase activity that was reduced by greater than 70%. In Levetiracetam addition, in cells coexpressing the prodomain mutants with APP, Aβ production was increased 1.5- to 3.5-fold. These results indicate that ADAM10 is indeed a LOAD susceptibility gene and suggest the intriguing possibility that the ADAM10 prodomain mutations reduce proteolytic

activity, even though they are located far from the active site of the enzyme. In their article in this issue of Neuron, the Tanzi group tested the role of the ADAM10 prodomain mutations in AD pathogenesis by generating transgenic mouse lines that express ADAM10 harboring the Q170H or R181G mutations in the brain ( Suh et al., 2013). They also made control mouse lines expressing an artificial dominant-negative (DN) mutation, E384A, or wild-type (WT) ADAM10. Multiple lines of each transgenic construct were created, and expression levels across the various transgenes were matched. In addition, the team crossed the different ADAM10 transgenic lines with the well-characterized APP transgenic mouse, Tg2576, to determine the effects of the ADAM10 prodomain mutations on Aβ generation and amyloid deposition in the brain.