The idea that lipid rafts may somehow modulate APP cleavage and hence affect the progression of AD has been around for over 10 years and previously reviewed (Cordy et al., 2006; Cheng et al., 2007; Vetrivel and Thinakaran, 2010) . APP itself is not generally a raft protein, although a small proportion of APP is localized in lipid rafts (Parkin et al., 1999) . Regulation of APP raft localization has been suggested to involve an interaction between the C-terminus of APP and flotillin-1 (Chen et al., 2006) . A more recent study suggested that flotillin-2 may also act as a scaffolding protein, clustering APP in lipid rafts. Schneider et al. (2008) postulated that a transient interaction between APP and flotillin-2 may regulate endocytosis of APP, which is important for its processing. It has also been suggested that another raft component, cholesterol, has a role in binding APP promoting its raft localization (Beel et al., 2010) although it was earlier proposed that one of the physiological functions of APP and Aβ is to control cholesterol transport (Yao and Papadopoulos, 2002) . There is also evidence that the adaptor protein Disabled1 (Dab1) interacts with APP regulating its processing and that the glycoprotein reelin promotes interaction of APP and Dab1 and their localization to lipid rafts involving phosphorylation by Fyn kinase (Hoe et al., 2009; Minami et al., 2011) . APP trafficking to the lipid rafts was shown to be dependent on the low-density lipoprotein receptor-related protein (LRP) which also promotes BACE1-APP interaction (Yoon et al., 2007) . On the other hand it was also demonstrated that ApoER2, a member of the low density lipoprotein receptor (LDL-R), negatively affects APP internalization and its expression stimulates Aβ production by shifting the proportion of APP from the non-raft region to the raft membrane domains (Fuentealba et al., 2007) . www.frontiersin.org FIGURE 1 | Schematic representation of APP processing and role of its products in AD pathology. The proteolytic processing of the large, transmembrane, amyloid precursor protein (APP) occurs in two distinct amyloidogenic and non-amyloidogenic pathways. The amyloidogenic pathway involves the sequential cleavage of APP by an aspartic proteinase, β-secretase, which releases a soluble ectodomain (sAPPβ) and the C-terminal fragment CTF99. This, in turn, is cleaved by another aspartic proteinase, γ-secretase, generating the transcriptional regulator APP intracellular domain (AICD), and releasing the 39-42 amino acid amyloid-β peptide (Aβ). Due to its very high ability to aggregation, Aβ forms dimers, trimers, and higher level oligomers which are toxic to cells and cause neuronal death. Formation of amyloid plaques from Aβ aggregates in complex with other proteins is a hallmark of AD but is considered as a scavenging process. In the non-amyloidogenic pathway APP molecules are cleaved at the α-secretase site within the Aβ-domain releasing a soluble ectodomain sAPPα and the C-terminal fragment CTF83. Proteolytic cleavage of CTF83 by γ-secretase releases AICD and p3 fragment whose functions are still unknown. The AICD fragment produced in the amyloidogenic pathway binds to a stabilizing factor Fe65 and in a complex with other factors (the histone acetyl transferase, Tip60, and a Mediator complex subunit Med12) can act as transcription factor regulating expression of a variety of genes, including an Aβ-degrading enzyme neprilysin. This process was found to be specific to the neuronal APP 695 isoform. AICD produced in the non-amyloidogenic pathway and from other APP isoforms (APP 751 and APP 770 ) is most likely to be degraded (e.g., by some intracellular proteases, e.g., insulin-degrading enzyme). Soluble APP ectodomains, sAPPα, and sAPPβ, have been shown to have neuroprotective properties.