Accumulation and aggregation of amyloid β-protein in late endosomes of Niemann-Pick type C cells
Accumulation and aggregation of amyloid β-protein in late endosomes of Niemann-Pick type C cells
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DOI：
10.1074/jbc.m009598200
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发表时间：
2001-02-09
影响因子：
4.8
通讯作者：
Ihara, Y
中科院分区：
文献类型：
--
作者：
Yamazaki, T;Chang, TY;Ihara, Y
越来越多的证据表明，胆固醇代谢通过影响淀粉样β蛋白（A β）代谢与阿尔茨海默病易感性有关。然而，胆固醇和A β之间精确的细胞连接位点尚未明确。为了解决这个问题，我们研究了尼曼-匹克C型（NPC）模型细胞和NPC突变细胞，这些细胞显示出异常的胆固醇运输。我观察到在NPC模型细胞和突变细胞的晚期内体中显著的A β积累，其中胆固醇积累，并且在NPC小鼠脑中显著积累。这种A β积累不依赖于其通过内吞途径的组成性分泌和产生。此外，其特征在于A β 42的显著优势和在SDS中的不溶性，表明在晚期内体中存在聚集的A β。最重要的是，A β积累与晚期内体中的胆固醇水平相结合。因此，NPC细胞的晚期内体是聚集的A β 42和胆固醇一样的新池，表明聚集的A β和胆固醇之间的直接相互作用。
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.