title: Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells.
abstract: There is growing evidence suggesting that cholesterol metabolism is linked to susceptibility to Alzheimer's disease by influencing amyloid beta-protein (Abeta) metabolism. However, the precise cellular linkage sites between cholesterol and Abeta 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 Abeta 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 Abeta accumulation was independent of its constitutive secretion and production through an endocytic pathway. In addition, it is characterized by a marked predominance of Abeta42 and insolubility in SDS, suggesting the presence of aggregated Abeta in late endosomes. Most importantly, Abeta accumulation is coupled with the cholesterol levels in late endosomes. Thus, late endosomes of NPC cells are a novel pool of aggregated Abeta42 as well as cholesterol, suggesting a direct interaction between aggregated Abeta and cholesterol.
authors.affiliation: Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.forename: T Y
authors.initials: TY
authors.lastname: Chang
authors.forename: C
authors.initials: C
authors.lastname: Haass
authors.forename: Y
authors.initials: Y
authors.lastname: Ihara
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000736:Androstenes; D000924:Anticholesteremic Agents; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol