The amyloid-degrading enzyme, NEP, has been shown to be partially associated with lipid rafts in human synoviocytes in "ectopeptidase-rich membrane microdomains" (Riemann et al., 2001) , and also in pre-B and B cell lines (Nalm-6 and Raji; Angelisová et al., 1999) . By targeting NEP to different intracellular www.frontiersin.org compartments of neurons, including the lipid rafts, Hama and colleagues demonstrated that the endogenous targeting signal in wild-type NEP is well optimized for the overall neuronal clearance of Aβ (Hama et al., 2004) . Only the mature, fully glycosylated form of NEP, preferentially in its dimerized form, can be found in lipid rafts in direct association with phosphatidylserine (Hama et al., 2004) . These authors also suggested that the localization of NEP in different intracellular compartments may be involved in the metabolism of distinct pools of Aβ and that the endogenous targeting signal in wild-type NEP is well optimized for the overall neuronal clearance of Aβ. The partitioning of NEP into lipid rafts has also recently been confirmed by Sato and colleagues . Although another Aβ-degrading enzyme, insulysin (insulin-degrading enzyme, IDE), is primarily a cytosolic protein it is also, in part, associated with lipid rafts where it may facilitate Aβ clearance (Bulloj et al., 2008) .