Lipid rafts have been defined as islands of highly ordered saturated lipids and cholesterol that are laterally mobile in the plane of a more disordered fluid bilayer of largely unsaturated lipids [4-6]. Because of their ability to segregate functional proteins, lipid rafts have been proposed to play a central role in many cellular processes, including intracellular signaling and protein and lipid sorting [4,5]. In particular, Simons and Ikonen in 1997 postulated that, in polarized epithelial cells, rafts can act as sorting platforms for inclusion of proteins into apical post-trans-Golgi network (TGN) sorting vesicles. Later studies subsequently provided evidence for the role of lipid rafts in signaling, as in the case of IgE receptor (FcRI) and T-cell antigen receptor (TCR) [7,8].
Association with detergent-resistant membranes (DRM) is a useful criterion to estimate whether a protein associates with lipid rafts . After solubilization of membranes or cells with Triton X-100 at 4 °C, raft-associated proteins and lipids remain insoluble and can then be floated to low density by sucrose density gradient centrifugation. If cholesterol is extracted by using methyl-b-cyclodextrin (mbCD) or is complexed by saponin, the raft proteins usually (but not always) become detergent-soluble .
Constitutive raft residents include glycophosphatidylinositol (GPI)-anchored proteins (e. g., the prion protein), double acylated proteins (e. g., tyrosine kinases of the Src family), palmitate-anchored proteins and transmembrane proteins (e.g., b-secretase; BACE) .
One source of confusion in the field of rafts has been the inter-relationship between rafts and caveolae. Indeed, for a long time these two terms have been used interchangeably. However, this issue has now been clarified by the analysis of caveolin knockout mice [10,11].
Caveolae appear as "smooth" uncoated-pits of 50- to 100-nm flask-shaped invaginations of the plasma membrane, originally identified by electron microscopy in a wide variety of tissues and cell types [12,13]. They represent a morphologically identifiable subset of lipid rafts identified by the coat protein, caveolin. Whilst the biochemical composition of lipid rafts and caveolae is thought to overlap, these microdomains are not equivalent .
Caveolar invagination is possibly driven by the polymerization of caveolins, of which there are three types: caveolin-1, -2, and -3. Caveolin-1 appears to have a central role in the formation of caveolae, because it was shown that cells without caveolin-1 lacked morphological caveolae, and that reintroduction of the protein was sufficient to generate caveolae [15,16].
Caveolae usually remain attached to the cell surface, but their internalization can be stimulated under certain conditions; for example, by Simian virus-40 (SV40)  or by treatment with the phosphatase inhibitor okadaic acid [18,19].
Both caveolae and rafts mediate the internalization of sphingolipids and sphingo-lipid-binding toxins, GPI-anchored proteins , and the autocrine motility factor (AMF).
Internalizations via caveolae or via lipid rafts are fundamentally similar processes, defined by their clathrin independence and sensitivity to cholesterol depletion. However, the cholesterol-dependent invagination of rafts occurs independently of caveolin-1 and of dynamin 2, a GTPase, localized at the neck of the caveolae  which regulates their internalization. Interestingly, in some cases caveolin-1 acts as a negative regulator of the budding of caveolar invaginations but caveolae become competent for endocytosis after specific signalling stimuli .
Caveolae/raft dysfunction has been implicated recently in the pathogenesis of different human diseases. Several groups of pathogens, including bacteria, prions, viruses, and parasites appear to hijack lipid rafts during internalization [23-25]. In this chapter, we illustrate the proposed role of lipid rafts in the trafficking and processing of PrPc and APP and in the pathogenesis of their related diseases.
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