Rajendran Lawrence, Honsho Masanori, Zahn Tobias R, Keller Patrick, Geiger Kathrin D, Verkade Paul, Simons Kai
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7. doi: 10.1073/pnas.0603838103. Epub 2006 Jul 12.
Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of beta-amyloid (Abeta) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The Abeta peptide is formed by the amyloidogenic 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 Abeta. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated Abeta is released into the extracellular milieu are not clear. Here, we show that beta-cleavage occurs in early endosomes followed by routing of Abeta to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of Abeta 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.
尽管阿尔茨海默病（AD）的确切病因仍存在争议，但目前的共识是，老年斑中β-淀粉样蛋白（Aβ）肽的积累是该疾病进展的标志之一。Aβ肽是由淀粉样前体蛋白（APP）经β-和γ-分泌酶进行淀粉样生成性切割形成的。内吞系统与导致Aβ形成的切割过程有关。然而，淀粉样生成性分泌酶进行切割的细胞内区室的身份以及细胞内产生的Aβ释放到细胞外环境中的机制尚不清楚。在此，我们表明在HeLa细胞和N2a细胞中，β-切割发生在早期内体中，随后Aβ被转运至多囊泡体（MVBs）。随后，一小部分Aβ肽可与外泌体一起从细胞中分泌出来，外泌体是MVBs的腔内囊泡，由于MVBs与质膜融合而释放到细胞外空间。研究发现外泌体蛋白在AD患者脑的斑块中积累，提示其在AD发病机制中发挥作用。
