Amyloid beta-peptides (A beta) are centrally involved in the pathogenesis of Alzheimer's disease. Using secretory phospholipase A2 (PLA2) from porcine pancreas as a model and in the presence of a limiting Ca2+ concentration of approximately 50 nM, the synthetic peptide A beta 1-42 activates the hydrolysis of the pyrene-labeled acidic phospholipid analog 1-palmitoyl-2-[(pyren-1-yl)]hexanoyl-sn-glycero-3-phosphoglycerol (PPHPG) maximally 2.3-fold, whereas an inhibition of PLA2 action by 50% on the corresponding phosphatidylcholine derivative (PPHPC) was observed. The above effects were evident at 0.24 nM A beta 1-42 corresponding to A beta 1-42:phospholipid and A beta 1-42:PLA2 molar ratios of 1:10 650 and 1:7.6, respectively. The presence of 10 mol % 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) in PPHPC reversed the inhibitory effect of A beta 1-42 peptide and for these vesicles the hydrolytic activity of PLA2 toward the fluorescent phosphatidylcholine was enhanced approximately 1.8-fold by A beta 1-42. In contrast, inclusion of 10 mol % POPG into PPHPG did not influence either the hydrolytic rate toward the latter lipid or the activating effect of A beta 1-42. Ca2+ concentrations exceeding 15 microM abolished the enhancing effect of A beta 1-42 on the hydrolysis of PPHPG whereas a slight activation of PPHPC hydrolysis now became evident. With limiting [Ca2+] preaggregated A beta 1-42 enhanced the hydrolysis of both PPHPG as well as PPHPC but the peptide concentrations required were higher by 3-4 orders of magnitude. The synthetic peptide A beta 25-35 corresponding to the hydrophobic membrane-spanning segment of the beta amyloid precursor protein activated PLA2 when using PPHPG as a substrate; however, compared to A beta 1-42 the extent of activation was less (approximately 2-fold) and required higher (1 nM) peptide. A beta 25-35 did not affect the hydrolysis of the phosphatidylcholine derivative. The hydrophilic peptide A beta 1-28 had no effect on PLA2-catalyzed hydrolysis of either PPHPG or PPHPC under the conditions used in the present study. Interestingly, the above activating effects of A beta 1-42 and A beta 25-35 on PLA2-catalyzed hydrolysis of the acidic phospholipid substrate parallel their toxicity on cultured neurons whereas A beta 1-28 had no influence either on cultured cells or on PLA2 activity.