Modulation of proteolytic processing by glycosphingolipids generates amyloid β-peptide

Abstract

Extracellular amyloid β-peptide (Aβ) deposits in the brain are characteristic of Alzheimer's disease. Proteolytic cleaving of amyloid precursor protein (APP) by β- and α-secretases generate these deposits. The cleavage by those secretases occurs predominantly in post-Golgi secretory and endocytic compartments and is influenced by cholesterol, indicating a role of the membrane lipid composition in APP processing. To analyze the function of glycosphingolipids (GSLs) in the proteolytic processing of APP and the generation of Aβ, we inhibited glycosylceramide synthase, the first enzyme in GSL biosynthesis pathway. The depletion of GSLs markedly reduced the secretion of endogenous APP in different cell types, including human neuroblastoma SH-SY5Y cells. Conversely, the addition of exogenous brain gangliosides to cultured cells increased the levels of both cellular and secreted APP. Importantly, depletion of GSLs strongly decreased the secretion of Aβ. Thus, enzymes involved in GSL metabolism might represent targets to inhibit Aβ production. © Springer-Verlag Tokyo 2006. All rights reserved.