APP is a type I integral membrane protein. It exists in three isoforms (APP 695 , APP 751 , and APP 770 ), generated from differential splicing of exons 7 and 8 (Sandbrink et al., 1996) . Exon 7 is homologous to protease inhibitors of the Kunitz type (KPI domain), while exon 8 is related to the MRC OX-2 antigen in thymocytes (Kitaguchi et al., 1988; Sandbrink et al., 1996) . APP 695 lacks both KPI and OX-2 domains, while APP 751 only lacks the OX-2 domain (Henriques et al., 2007) . In terms of distribution, APP mRNA is expressed in almost every tissue, where only the isoform ratio differs (Araki et al., 1991) . It is APP 695 that predominates in neurons (Gralle and Ferreira, 2007) . There are two proteolytic pathways of APP processing (Figure 1) . Amyloidogenic processing involves sequential cleavage of APP by βand γ-secretases (for review see Zhang et al., 2012) . This process ultimately releases Aβ peptide, responsible in large part for the pathogenesis of AD and a soluble ectodomain, sAPPβ. The second, non-amyloidogenic, pathway involves α-secretase cleavage of APP. This cleavage occurs between Lys16 and Leu17, within the Aβ region (Allinson et al., 2003) and precludes formation of Aβ. There is also the release of the large, soluble ectodomain, the neuroprotective sAPPα, which is shed from the cell surface (Allinson et al., 2004) and has been found in the CSF (Palmert et al., 1989) .