Altered apolipoprotein E glycosylation is associated with Aβ(42) accumulation in an animal model of Niemann-Pick Type C disease

P>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, including the link between aberrant cholesterol metabolism and amyloid-beta (A beta) deposition. Apolipoprotein E (apoE) is highly expressed in the brain and plays a pivotal role in cholesterol metabolism. ApoE can also modulate A beta production and clearance, and it is a major genetic risk factor for Alzheimer's disease. Although apoE is glycosylated, the functional significance of this chemical alteration on A beta catabolism is unclear. In this study using an NPC animal model, we detect specific changes in apoE glycosylation that correlate with increased A beta(42) accumulation prior to the appearance of neurological abnormalities. This suggests that increased apoE expression could be a compensatory response to the increased A beta(42) deposition in NPCnih mice. We also observe what appears to be a simplification of the glycosylation process on apoE during neurodegeneration.