Lipid rafts affect APP processing not only through favoring interactions between APP and BACE-1 but also by promoting endocytosis of APP. This process was shown to be APP isoform-dependent with the neuronal APP 695 isoform to be mostly processed via the β-secretase pathway whereas APP 751 and APP 770 mainly undergo α-secretase cleavage (Belyaev et al., 2010) . Some of the earliest work about subcellular localization of APP processing indicated that sAPPβ could be detected in neuronal NT2N cell lysates with the absence of sAPPα or p3 fragments. This suggested an intracellular β-secretase pathway (Chyung et al., 1997; Hartmann et al., 1997) . It is worth noting that the β-secretase pathway operates differently with wild-type APP (wtAPP) and APP carrying the Swedish mutation (APP Sw ; Haass et al., 1995; Griffiths et al., 2011 ). An alternative trafficking pathway has been recently reported, whereby APP can bypass endosomes and be trafficked directly to the lysosomes. This, though, does not occur with either APP Sw or APP London variants suggesting that these mutations affect APP transit (Lorenzen et al., 2010) .