Influence of membrane lipid metabolism on cerebral amyloid deposition and neurodegeneration.

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We examined the ultrastructure of rafts in rat brain tissue by pre-embedding immunoelectron microscopy using flotillin-1 antibody, which is biochemical marker of lipid rafts, and BCθ, which is nicked and biotinylated θ-toxin, and binds to membrane cholesterol of rafts. Flotillin-1-and BCθ-labeled areas were patchy and prominent on the plasma membranes of small processes and synapses in the neuropil. The size of flotillin-1 labeling was 40 to 200nm.In addition, the membrane of lysosome and Golgi apparatus were frequently labeled for flotillin-1 with a patchy pattern. Flotillin-1 and BCθ were mostly colocalized in double immunolabeling on a part of the plasma membranes of small processes and secondary lysosome membranes. We first indicate that flotillin-1 localizes to BCθ-positive cholesterol-rich membrane microdomains in vivo, and that flotillin-1 and BCθ could be an ultrastructural rafts marker in neural tissue. We also examined the relation between lipid raft and cerebral β-amyloid deposition in the Tg2576 transgenic mouse.Moreover, we found a striking difference in the distribution of membrane cholesterol. ApoE4 knock-in mice showed an approximately 2-fold increase in exofacial leaflet cholesterol compared with apoE3 knock-in mice and wild-type mice.