Cellular Membrane Composition Defines Aβ-Lipid Interactions

Abstract

Alzheimer's disease pathology has demonstrated amyloid plaque formation associated with plasma membranes and the presence of intracellular amyloid-β (Aβ) accumulation in specific vesicular compartments. This suggests that lipid composition in different compartments may play a role in Aβ aggregation. To test this hypothesis, we have isolated cellular membranes from human brain to evaluate Aβ40/42-lipid interactions. Plasma, endosomal, lysosomal, and Golgi membranes were isolated using sucrose gradients. Electron microscopy demonstrated that Aβ fibrillogenesis is accelerated in the presence of plasma and endosomal and lysosomal membranes with plasma membranes inducing an enhanced surface organization. Alternatively, interaction of Aβ with Golgi membranes fails to progress to fibril formation, suggesting that Aβ-Golgi head group interaction stabilizes Aβ. Fluorescence spectroscopy using the environment-sensitive probes 1,6-diphenyl-1,3,5-hexatriene, laurdan, N-ε-dansyl-L-lysine, and merocyanine 540 demonstrated variations in the inherent lipid properties at the level of the fatty acyl chains, glycerol backbone, and head groups, respectively. Addition of Aβ40/42 to the plasma and endosomal and lysosomal membranes decreases the fluidity not only of the fatty acyl chains but also the head group space, consistent with Aβ insertion into the bilayer. In contrast, the Golgi bilayer fluidity is increased by Aβ40/42 binding which appears to result from lipid head group interactions and the production of interfacial packing defects.