Cellular membrane composition defines A beta-lipid interactions.
Alzheimer's disease pathology has demonstrated amyloid plaque formation associated with plasma membranes and the presence of intracellular amyloid-beta (A beta) accumulation in specific vesicular compartments. This suggests that lipid composition in different compartments may play a role in A beta aggregation. To test this hypothesis, we have isolated cellular membranes from human brain to evaluate A beta 40/42-lipid interactions. Plasma, endosomal, lysosomal, and Golgi membranes were isolated using sucrose gradients. Electron microscopy demonstrated that A beta fibrillogenesis is accelerated in the presence of plasma and endosomal and lysosomal membranes with plasma membranes inducing an enhanced surface organization. Alternatively, interaction of A beta with Golgi membranes fails to progress to fibril formation, suggesting that A beta-Golgi head group interaction stabilizes A beta. Fluorescence spectroscopy using the environment-sensitive probes 1,6-diphenyl-1,3,5-hexatriene, laurdan, N-epsilon-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 A beta 40/42 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 A beta insertion into the bilayer. In contrast, the Golgi bilayer fluidity is increased by A beta 40/42 binding which appears to result from lipid head group interactions and the production of interfacial packing defects.
Waschuk
S A
SA
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
Elton
E A
EA
Darabie
A A
AA
Fraser
P E
PE
McLaurin
J A
JA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D016880:Anisotropy; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D019281:Dimerization; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005456:Fluorescent Dyes / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D011744:Pyrimidinones / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D008055:Lipids; D010455:Peptides; D010743:Phospholipids; D011744:Pyrimidinones; C003954:merocyanine dye