Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid beta-protein.

The assembly of amyloid beta-protein into fibrils is an initial event of Alzheimer's disease (AD). Previous studies suggest that ganglioside-bound amyloid beta-protein (Abeta), GAbeta, is an endogenous seed for amyloid in Alzheimer's disease (AD) brain and that GAbeta is generated in the membrane microdomains, comprising cholesterol, sphingomyelin (SM) and GM1 ganglioside. In this study, we showed that the GAbeta-dependent amyloidogenesis was accelerated on the surface of PC12 cells that had been pretreated with a sphingomyelinase inhibitor. Conversely, the enhanced GAbeta-dependent amyloidogenesis under the endocytic dysfunction, which is one of the cell-pathological features of AD, was suppressed by pretreatment with a SM synthase inhibitor. These suggest that SM is one of the key molecules for GAbeta generation and further imply that the interaction of Abeta with membrane lipids is critical in amyloid fibrillization in the brain. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.