, Volume 25, Issue 3, pp 423-429

Interaction of Amyloid Beta-Protein with Anionic Phospholipids: Possible Involvement of Lys28 and C-Terminus Aliphatic Amino Acids

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Abstract

Fibrillar amyloid beta-protein (Aβ) is the major protein of amyloid plaques in the brains of patients with Alzheimer's disease (AD). The mechanism by which normally produced soluble Aβ gets fibrillized in AD is not clear. We studied the effect of neutral, zwitterionic, and anionic lipids on the fibrillization of Aβ 1-40. We report here that acidic phospholipids such as phosphatidic acid, phosphatidylserine, phosphatidylinositol (PI), PI 4-phosphate, PI 4,5-P2 and cardiolipin can increase the fibrillization of Aβ, while the neutral lipids (diacylglycerol, cholesterol, cerebrosides), zwitterionic lipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin) and anionic lipids lacking phosphate groups (sulfatides, gangliosides) do not affect Aβ fibrillization. Aβ was found to increase the fluorescence of 1-acyl-2-[12-[ (7-nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphate (NBD-PA) in a concentration-dependent manner, while no change was observed with 1-acyl-2-[12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphoethanolamine (NBD-PE). Under similar conditions, other proteins such as apolipoprotein E, gelsolin and polyglutamic acid did not interact with NBD-PA. The order of interaction of amyloid β-peptides with NBD-PA was Aβ 1-43 = Aβ 1-42 = Aβ 17-42 > Aβ 1-40 = Aβ 17-40. Other Aβ peptides such as Aβ 1-11, Aβ 1-16, Aβ 1-28, Aβ 1-38, Aβ 12-28, Aβ 22-35, Aβ 25-35, and Aβ 31-35 did not increase the NBD-PA fluorescence. These results suggest that phosphate groups, fatty acids, and aliphatic amino acids at the C-terminus end of Aβ 1-40/Aβ 1-42 are essential for the interaction of Aβ with anionic phospholipids, while hydrophilic Aβ segment from 1-16 amino acids does not participate in this interaction. Since positively charged amino acids in Aβ are necessary for the interaction with negatively charged phosphate groups of phospholipids, it is suggested that Lys28 of Aβ may provide anchor for the phosphate groups of lipids, while aliphatic amino acids (Val-Val-Ile-Ala) at the C-terminus of Aβ interact with fatty acids of phospholipids.