Alzheimer's disease β-amyloid peptides are released in association with exosomes
Alzheimer's disease β-amyloid peptides are released in association with exosomes
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DOI：
10.1073/pnas.0603838103
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发表时间：
2006-07-25
影响因子：
11.1
通讯作者：
Simons, Kai
中科院分区：
文献类型：
--
作者：
Rajendran, Lawrence;Honsho, Masanori;Simons, Kai
虽然阿尔茨海默病（AD）的确切病因是一个有争议的话题，但共识是β-淀粉样蛋白（A β）肽在老年斑中的积累是疾病进展的标志之一。A β肽由β-和γ-分泌酶对淀粉样前体蛋白（APP）的淀粉样裂解形成。内吞系统与导致A β形成的裂解有关。然而，淀粉样蛋白生成分泌酶裂解的细胞内区室的身份和细胞内产生的AP释放到细胞外环境中的机制尚不清楚。在这里，我们表明，β-裂解发生在早期的内涵体，然后路由的A β多泡体（MVBs）在HeLa和N2 a细胞。随后，AP肽的一小部分可以从与外来体、MVB的腔内囊泡结合的细胞中分泌，所述外来体、MVB的腔内囊泡由于MVB与质膜融合而释放到细胞外空间中。发现外泌体蛋白在AD患者脑的斑块中积累，表明在AD的发病机制中起作用。
Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of beta-amyloid (A beta) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The A beta peptide is formed by the amyloiclogenic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. The endocytic system has been implicated in the cleavages leading to the formation of A beta. However, the identity of the intracellular compartment where the amyloiclogenic secretases cleave and the mechanism by which the intracellularly generated AP is released into the extracellular milieu are not clear. Here, we show that beta-cleavage occurs in early endosomes followed by routing of A beta to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of AP peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD.