Elevation in sphingomyelin synthase activity is associated with increases in amyloid-beta peptide generation.

ABSTRACT

A pathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-beta peptide (Aß) plaques in the brain. Aß is derived from a sequential proteolysis of the transmenbrane amyloid precursor protein (APP), a process which is dependent on the distribution of lipids present in the plasma membrane. Sphingomyelin is a major membrane lipid, however its role in APP processing is unclear. Here, we assessed the expression of sphingomyelin synthase (SGMS1; the gene responsible for sphingomyelin synthesis) in human brain and found that it was significantly elevated in the hippocampus of AD brains, but not in the cerebellum. Secondly, we assessed the impact of altering SGMS activity on Aß generation. Inhibition of SGMS activity significantly reduced the level of Aß in a dose- and time dependent manner. The decrease in Aß level occurred without changes in APP expression or cell viability. These results when put together indicate that SGMS activity impacts on APP processing to produce Aß and it could be a contributing factor in Aß pathology associated with AD.