Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity
Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity
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DOI：
10.1073/pnas.0904532106
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Faendrich, Marcus
中科院分区：
文献类型：
--
作者：
Friedrich, Ralf P.;Tepper, Katharina;Faendrich, Marcus
细胞外淀粉样斑块的形成是几种使人衰弱的人类疾病（包括阿尔茨海默病）背后常见的病理生化事件。大量证据表明，阿尔茨海默病的损伤主要由Aβ肽的小寡聚淀粉样形式引起，但致病的确切机制仍有待确定。利用一种可重复导致阿尔茨海默病Aβ淀粉样斑块形成的细胞培养系统，我们在此表明，单个淀粉样斑块的形成是一个模板依赖的过程，该过程关键涉及具有内吞或吞噬能力的细胞的存在。内化的Aβ肽被分选到多泡体中，在那里纤维生长出来，从而穿透囊泡膜。在斑块形成时，细胞发生死亡，细胞内淀粉样结构被释放到细胞外空间。这些数据暗示了一种机制，即Aβ的致病活性至少部分归因于细胞内聚集体。
The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer's disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of A beta peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer's A beta amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis-or phagocytosis-competent cells. Internalized A beta peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of A beta is attributed, at least in part, to intracellular aggregates.