Accumulation and Aggregation of Amyloid β-Protein in Late Endosomes of Niemann-Pick Type C Cells*

There is growing evidence suggesting that cholesterol metabolism is linked to susceptibility to Alzheimer's disease by influencing amyloid β-protein (Aβ) metabolism. However, the precise cellular linkage sites between cholesterol and Aβ have not yet been clarified. To address this issue, we investigated Niemann-Pick type C (NPC) model cells and NPC mutant cells, which showed aberrant cholesterol trafficking. We observed a remarkable Aβ accumulation in late endosomes of both NPC model cells and mutant cells where cholesterol accumulates and a significant accumulation in the NPC mouse brain. This Aβ accumulation was independent of its constitutive secretion and production through an endocytic pathway. In addition, it is characterized by a marked predominance of Aβ42 and insolubility in SDS, suggesting the presence of aggregated Aβ in late endosomes. Most importantly, Aβ accumulation is coupled with the cholesterol levels in late endosomes. Thus, late endosomes of NPC cells are a novel pool of aggregated Aβ42 as well as cholesterol, suggesting a direct interaction between aggregated Aβ and cholesterol.