In addition to being the precursor to Aβ, a number of physiological functions have been attributed to APP, including, but not limited to, synapse formation, neuronal survival, and neuritic outgrowth (De Strooper and Annaert, 2000; Mattson, 1995, 1997; Nunan et al., 2001; Russo et al., 1998; Turner et al., 2003). APP belongs to a highly conserved gene family including the amyloid precursor-like proteins, APLP1 and APLP2 (Anliker and Muller, 2006). It is encoded on chromosome 21 and is alternatively spliced into 3 main isoforms, APP695, APP751, and APP770. Individuals with Down syndrome (trisomy 21) or inherited cases of familial AD with point mutations in the APP gene invariably develop AD pathology (Epstein, 1990; Potter, 1991). This link of APP to AD pathology and the many putative functions of APP in neurons led to the establishment of many invertebrate and transgenic mouse models, both knock-in (4 with truncated alleles and 2 with C-terminal point mutation alleles) and knock-out (2 KO and 2 conditional), that suffer from various defects and abnormalities (reviewed in (Guo et al., 2011). One APP KO mouse generated
