molgen.ua.ac.be/ADMutations). FAD-linked PS mutations cause neomorphic protease activity, leading to increased production of Aβ42, the more Ruxolitinib ic50 hydrophobic and aggregation-prone peptides, compared to Aβ40 ( Figure 3A) ( De Strooper and Annaert, 2010). The prevailing amyloid hypothesis posits that accumulation of Aβ42 peptides triggers a pathogenic cascade, leading to neurodegeneration ( Hardy and Higgins, 1992). Therefore, it is thought that inhibition of γ-secretase activity may help to lower Aβ production serving as a therapy for AD. This therapeutic approach is tempered by the finding that conditional inactivation of PS1/2 in the adult mouse brain

causes progressive memory loss check details and neurodegeneration ( Saura et al., 2004 and Zhang et al., 2009), raising the possibility that γ-secretase activity is required for maintaining normal brain function ( Shen and Kelleher, 2007). Notch and APP represent only two examples of an expanding list of γ-secretase substrates that are known to undergo sequential proteolytic cleavage. Although this list includes many axon guidance molecules, the functional consequences of γ-secretase cleavage are best defined for the Netrin receptor DCC (Table 1). The extracellular

domain of DCC is first cleaved by a metalloprotease to create a membrane-tethered DCC stub. Under normal conditions the DCC stub is present at low concentrations because it is rapidly cleaved by γ-secretase, releasing the intracellular domain (ICD) from the membrane (Figure 3C). In vitro studies have shown that inhibition of γ-secretase activity results in accumulation of DCC stubs in cell membranes and is correlated with enhanced neurite outgrowth in cultured neuroblastoma cells (Figure 3E) (Parent et al., 2005 and Taniguchi et al., 2003). Although PS1 and PS2 mutant mice have been studied for more than a decade, the in vivo function of γ-secretase cleavage of guidance

molecules such as DCC was uncertain, perhaps because of the diversity of PS functions ( Donoviel et al., 1999 and Shen et al., 1997). A role for PS1 in axon guidance was first revealed in a mouse ENU mutagenesis screen to identify genes involved in embryonic motor neuron axon pathfinding ( Bai et al., Endonuclease 2011). Bai and colleagues discovered that motor axons in the Columbus mutant grew into the spinal cord floor plate at the midline rather than exiting laterally through their normal ventral root sites and found that this phenotype is caused by a mutation in the PS1 gene. Through a series of in vivo and in vitro experiments they linked this axon guidance phenotype to a defect in γ-secretase processing of DCC, causing motor neurons to inappropriately become attracted to the Netrin-1 produced by the floor plate ( Bai et al., 2011).