T. Yamazaki et al., Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-Pick type C cells, J BIOL CHEM, 276(6), 2001, pp. 4454-4460
There is growing evidence suggesting that cholesterol metabolism is linked
to susceptibility to Alzheimer's disease by influencing amyloid beta -prote
in (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 cel
ls where cholesterol accumulates and a significant accumulation in the NPC
mouse brain. This A beta accumulation was independent of its constitutive s
ecretion and production through an endocytic pathway. In addition, it is ch
aracterized by a marked predominance of A beta 42 and insolubility in SDS,
suggesting the presence of aggregated A beta in late endosomes. Most import
antly, A beta accumulation is coupled with the cholesterol levels in late e
ndosomes. Thus, late endosomes of NPC cells are a novel pool of aggregated
A beta 42 as web as cholesterol, suggesting a direct interaction between ag
gregated A beta and cholesterol.