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

The assembly of amyloid β-protein into fibrils is an initial event of Alzheimer's disease (AD). Previous studies suggest that ganglioside-bound amyloid β-protein (Aβ), GAβ, is an endogenous seed for amyloid in Alzheimer's disease (AD) brain and that GAβ is generated in the membrane microdomains, comprising cholesterol, sphingomyelin (SM) and GM1 ganglioside. In this study, we showed that the GAβ-dependent amyloidogenesis was accelerated on the surface of PC12 cells that had been pretreated with a sphingomyelinase inhibitor. Conversely, the enhanced GAβ-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 GAβ generation and further imply that the interaction of Aβ with membrane lipids is critical in amyloid fibrillization in the brain.