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 beta -protein (A beta) metabolism. However, the precise cellular linkage sites between cholesterol and A beta 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. me observed a remarkable A beta 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 A beta accumulation was independent of its constitutive secretion and production through an endocytic pathway. In addition, it is characterized by a marked predominance of A beta 42 and insolubility in SDS, suggesting the presence of aggregated A beta in late endosomes. Most importantly, A beta accumulation is coupled with the cholesterol levels in late endosomes. Thus, late endosomes of NPC cells are a novel pool of aggregated A beta 42 as web as cholesterol, suggesting a direct interaction between aggregated A beta and cholesterol.