Down syndrome fibroblast model of Alzheimer-related endosome pathology - Accelerated endocytosis promotes late endocytic defects
Down syndrome fibroblast model of Alzheimer-related endosome pathology - Accelerated endocytosis promotes late endocytic defects
复制标题
DOI：
10.2353/ajpath.2008.071053
复制
发表时间：
2008-08-01
影响因子：
6
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Cataldo, Anne M.;Mathews, Paul M.;Nixon, Ralph A.
内吞功能障碍是阿尔茨海默病(AD)和唐氏综合征(DS)的早期病理改变。利用DS患者的原代成纤维细胞，我们探索了AD中改变的内细胞室之间的相互作用，并评估了它们在AD发病机制中的功能后果。我们发现，与AD和DS脑中的神经元一样，DS成纤维细胞表现出内吞、融合和循环增加，并将溶酶体水解酶运输到Rab5阳性的早期内吞体内。此外，用抗Rab7-和溶二磷脂酸的抗体鉴定的晚期内体数量增加，表现为扩大的核周空泡，类似于AD和DS脑中的神经元。在对照成纤维细胞中，当表达一个rab5或一个活性的rab5突变体增加内吞作用和内体融合时，可以诱导类似的Rab5、rab7和溶酶双磷脂酸阳性的内涵体增大，这表明持续的内吞激活会导致晚期的内吞功能障碍。相反，表达抑制细胞内摄取的Rab5突变体可以逆转DS成纤维细胞早期和晚期的内体异常。我们的结果表明，DS成纤维细胞概括了AD和DS的神经元内吞功能障碍，这表明早期内小体转运的增加可能是AD和DS脑内神经元发生下游内吞扰动的部分原因。
Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals, we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that, like neurons in both AD and DS brains, DS fibroblasts exhibit increased endocytic uptake, fusion, and recycling, and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover, late endosomes identified using antibodies to rab7- and lysobisphosphatidic acid increased in number and appeared as enlarged, perinuclear vacuoles, resembling those in neurons of both AD and DS brains. In control fibroblasts, similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant, suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely, expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS, suggesting that increased trafficking from early endosomes can account, in part, for downstream endocytic perturbations that occur in neurons in both AD and DS brains.