Distribution of Presenilins and Amyloid Precursor Protein (APP) in Detergent-Insoluble Membrane Domains

Until recently, the detergent insolubility of certain membrane-associated proteins was singularly attributed to an association with the cytoskeleton. However, in 1988 we observed that a number of glycosyl-phosphatidylinositol (GPI)-anchored proteins were resistant to solubilization by nonionic detergents such as Triton X-100 (1). This detergent insolubility is acquired as the proteins pass through the endoplasmic reticulum and on to the Golgi apparatus (2), and arises not from a direct interaction of the GPI-anchored proteins with cytoskeletal elements but as a result of the specific lipid composition of the membrane domains with which these proteins associate (3,4). Mammalian cell membranes contain hundreds of individual lipid species which can be grouped under several major headings (e.g., glycerophospholipids, sphingomyelins, ceramides, glycosphingolipids, and cholesterol) (2,5,6). Glycerophospholipids, such as phosphatidylcholine and phosphatidylethanolamine, predominate in the membrane milieu. Consequently, the bulk of the cell membrane is fluid and in a continual state of flux. However, the membrane domains with which GPI-anchored proteins associate are enriched with sphingolipids and cholesterol, making them less fluid than the membrane milieu (2,4). Such membrane domains have been referred to as "lipid rafts" (7) and there has been some controversy as to whether they exist in vivo or whether they form as an artefact of the procedures employed in their isolation (8). However, recent studies in both artificial lipid bilayers and living cell membranes using such techniques.