Fibrillar amyloid beta-protein (Abeta) is the major protein of amyloid plaques in the brains of patients with Alzheimer's disease (AD). The mechanism by which normally produced soluble Abeta gets fibrillized in AD is not clear. We studied the effect of neutral, zwitterionic, and anionic lipids on the fibrillization of Abeta 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 Abeta, while the neutral lipids (diacylglycerol, cholesterol, cerebrosides), zwitterionic lipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin) and anionic lipids lacking phosphate groups (sulfatides, gangliosides) do not affect Abeta fibrillization. Abeta 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 beta-peptides with NBD-PA was Abeta 1-43 = Abeta 1-42 = Abeta 17-42 > Abeta 1-40 = Abeta 17-40. Other Abeta peptides such as Abeta 1-11, Abeta 1-16, Abeta 1-28, Abeta 1-38, Abeta 12-28, Abeta 22-35, Abeta 25-35, and Abeta 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 Abeta 1-40/Abeta 1-42 are essential for the interaction of Abeta with anionic phospholipids, while hydrophilic Abeta segment from 1-16 amino acids does not participate in this interaction. Since positively charged amino acids in Abeta are necessary for the interaction with negatively charged phosphate groups of phospholipids, it is suggested that Lys28 of Abeta may provide anchor for the phosphate groups of lipids, while aliphatic amino acids (Val-Val-Ile-Ala) at the C-terminus of Abeta interact with fatty acids of phospholipids.