A novel action of Alzheimer's amyloid β-protein (Aβ):: Oligomeric Aβ promotes lipid release

Interactions between amyloid beta -protein (A beta) and lipids have been suggested to play important roles in the pathogenesis of Alzheimer's disease. However, the molecular mechanism underlying these interactions has not been fully understood. We examined the effect of A beta on lipid metabolism in cultured neurons and astrocytes and found that oligomeric A beta, but not monomeric or fibrillar A beta, promoted lipid release from both types of cells in a dose- and time-dependent manner. The main components of lipids released after the addition of A beta were cholesterol, phospholipids, and monosialoganglioside (GM1). Density-gradient and electron microscopic analyses of the conditioned media demonstrated that these A beta and lipids formed particles and were recovered from the fractions at densities of similar to1.08-1.18 g/ml, which were similar to those of high-density lipoprotein (HDL) generated by apolipoproteins. The lipid release mediated by A beta was abolished by concomitant treatment with Congo red and the PKC inhibitor, H7, whereas it was not inhibited with N-acetyl-L-cysteine. These A beta -lipid particles were not internalized into neurons, whereas HDL-like particles produced by apolipoprotein E were internalized. Our findings indicate that oligomeric A beta promotes lipid release from neuronal membrane, which may lead to the disruption of neuronal lipid homeostasis and the loss of neuronal function.