Yamazaki T, Chang T Y, Haass C, Ihara Y
Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Biol Chem. 2001 Feb 9;276(6):4454-60. doi: 10.1074/jbc.M009598200. Epub 2000 Nov 20.
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.
越来越多的证据表明，胆固醇代谢通过影响β-淀粉样蛋白（Aβ）代谢与阿尔茨海默病易感性相关。然而，胆固醇与Aβ之间精确的细胞连接位点尚未明确。为解决这一问题，我们研究了显示胆固醇转运异常的尼曼-匹克C型（NPC）模型细胞和NPC突变细胞。我们观察到在胆固醇积聚的NPC模型细胞和突变细胞的晚期内体中Aβ显著积聚，且在NPC小鼠脑中也有大量积聚。这种Aβ积聚与其通过内吞途径的组成性分泌和产生无关。此外，其特征是Aβ42明显占优势且不溶于十二烷基硫酸钠，提示晚期内体中存在聚集的Aβ。最重要的是，Aβ积聚与晚期内体中的胆固醇水平相关。因此，NPC细胞的晚期内体是聚集的Aβ42以及胆固醇的一个新库，提示聚集的Aβ与胆固醇之间存在直接相互作用。
