Interaction of amyloid beta-protein with anionic phospholipids: Possible involvement of Lys(28) and C-terminus aliphatic amino acids

Fibrillar amyloid beta-protein (A beta) is the major protein of amyloid pla ques in the brains of patients with Alzheimer's disease (AD). The mechanism by which normally produced soluble A beta gets fibrillized in AD is not cl ear. We studied the effect of neutral, zwitterionic, and anionic lipids on the fibrillization of A beta 1-40. We report here that acidic phospholipids such as phosphatidic acid, phosphatidylserine, phosphatidylinositol (PI), PI 4-phosphate, PI 4.5-P-2 and cardiolipin can increase the fibrillization of A beta, while the neutral lipids (diacylglycerol, cholesterol, cerebrosi des), zwitterionic lipids (phosphatidylcholine, phosphatidylethanolamine, s phingomyelin) and anionic lipids lacking phosphate groups (sulfatides, gang liosides) do not affect A beta fibrillization. A beta was found to increase the fluorescence of 1-acyl-2-[12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl) amin o] 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-b enzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphoethanolamine (NBD -PE). Under similar conditions, other proteins such as apolipoprotein E, ge lsolin and polyglutamic acid did not interact with NBD-PA. The order of int eraction of amyloid beta-peptides with NBD-PA was A beta 1-43 = A beta 1-42 = A beta 17-42 > A beta 1-40 = A beta 17-40. Other A beta peptides such as A beta 1-11, A beta 1-16, A beta 1-28, A beta 1-38, A beta 12-28, A beta 2 2-35, A beta 25-35, and A beta 31-35 did not increase the NBD-PA fluorescen ce. These results suggest that phosphate groups, fatty acids, and aliphatic amino acids at the C-terminus end of A beta 1-40/A beta 1-42 are essential for the interaction of A beta with anionic phospholipids, while hydrophili c A beta segment from 1-16 amino acids does not participate in this interac tion. Since positively charged amino acids in A beta are necessary for the interaction with negatively charged phosphate groups of phospholipids, it i s suggested that Lys(28) Of A beta may provide anchor for the phosphate gro ups of lipids, while aliphatic amino acids (Val-Val-Ile-Ala) at the C-termi nus of A beta interact with fatty acids of phospholipids.