Alzheimer's A beta(1-40) peptide modulates lipid synthesis in neuronal cultures and intact rat fetal brain under normoxic and oxidative stress conditions

The effect of amyloid beta (A beta), the major constituent of the Alzheimer 's (AD) brain on lipid metabolism was investigated in cultured nerve cells and in a fetal rat brain model. Differentiated (NGF) and undifferentiated P C12 cells or primary cerebral cell cultures were incubated with [C-14]aceta te in the absence or presence of A beta(1-40). Incorporation of label into lipid species was determined after lipid extraction and TLC separation. Pho sphatidylcholine (PC) and phosphatidylserine (PS) synthesis was increased b y A beta(1-40), in a dose dependent manner, an effect which was more pronou nced in differentiated PC12 cells. A significant proportion of radioactivit y (5-6%) was released into the medium with a radioactivity distribution sim ilar to that of the cellular lipids. Cholesterol and PC were the highest la beled medium lipids. Increasing A beta(1-40) concentration up to 0.1 mu g/m l in cerebral cells but not in PC12 cells, caused a relative increase (1.5 fold) in release of PS, while that of PE decreased. Stimulation of PS relea se may possibly be associated with apoptotic cell death. A beta(1-40) pepti de (5 mu g) was administered intraperitonealy into rat fetuses (18 days ges tation) along with [C-14]-acetate (2 mu Ci/fetus). After 24 h, the maternal -fetal blood supply was occluded for 20 min (ischemia) followed by 15 min r eperfusion. Fetuses were killed and liver and brain tissue subjected to lip id extraction and radioactivity determination after TLC. A beta(1-40) pepti de increased synthesis of different classes of lipids up to 20-40% in brain tissue compared to controls. Labeling of liver lipids was decreased by A b eta(1-40) by 20-30%. A general decrease in synthesis of lipids was observed after ischemia/reperfusion. Our data suggest that A beta(1-40) peptide reg ulates normal lipid biosynthesis but under ischemia it compromises it. The latter finding may confirm the oxidative stress etiology in AD and suggests that A beta(1-40) modulation of lipid metabolism may have Alzheimer's path ological relevance, particularly at high peptide concentrations.