Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models

Abstract

Heparan sulphate proteoglycans (HSPG) are central to numerous processes of the mammalian cell. The highly charged negative side chains of the heparan sulphate (HS) oligosaccharides are essential for the regulatory and structural functions of the proteoglycan. Synthetic HS compounds have potential therapeutic value due to their ability to mimic naturally occurring HS. Niemann-Pick disease type C (NPC) is a fatal childhood neurodegenerative disease with characteristic cholesterol and sphingolipid accumulation in the late endosome or lysosome. Alzheimer’s disease, another neurodegenerative disorder, shares alterations of cholesterol and amyloid β metabolism with NPC. In this study,a set of novel heparan sulphate compounds with a range of structures and oligosaccharide side groups with a variety of degrees of sulphation was investigated with regards to their effects on cholesterol and amyloid β metabolism in cell line models of these two diseases. Fluorescent staining of cholesterol and confocal microscopy showed highly sulphated compounds reduce the accumulation of cholesterol in the perinuclear lysosomal storage organelles in patient fibroblast cell lines. The compounds had no effect on secreted amyloid β levels or amyloid precursor protein levels in a neuronal cell line model of early onset Alzheimer’s disease. The mechanism of cholesterol reduction is unclear but may be related to a reduction in HSPG-associated endocytosis of LDL/cholesterol.