Effect of Apolipoprotein E glycosylation on lipoprotein and Aβ metabolism in an animal model for Niemann‐Pick Type C disease

Abstract

Neurodegeneration is the final cause of death in Niemann‐Pick Type C (NPC) disease, a cholesterol‐storage disorder. Accumulating evidence indicates that NPC may share common pathological mechanisms with Alzheimer's disease (AD), including the link between cholesterol and amyloid‐ß (Aß) deposition. However, the mechanisms underlying neurodegeneration in NPC is unclear. Apolipoprotein E (apoE) is highly expressed in the brain and plays a pivotal role in cholesterol metabolism. Altered apoE expression is associated with defective interaction with lipoproteins and causes hypercholesterolemia, a risk factor for AD. Moreover, ApoE polymorphism was found to modulate the susceptibility to develop AD by differentially binding to Aß and regulating their clearance. Earlier studies showed that ApoE is differentially sialylated but the functional significance of this chemical alteration on ApoE role in cholesterol homeostasis and Aß catabolism is unknown. In this study using an animal model of NPC, we will correlate the glycan profile on neuronal ApoE with Aß accumulation and cholesterol dysfunction at different stages of disease development. We will also profile the changes in the biochemistry of lipoprotein metabolism and in the expression of enzymes involved in Aß metabolism during the neurodegenerative cascade.