期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2012
卷号：109
期号：30
页码：E2077-E2082
DOI：10.1073/pnas.1208635109
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Amyloid precursor protein (APP) is processed sequentially by the {beta}-site APP cleaving enzyme and {gamma}-secretase to generate amyloid {beta} (A{beta}) peptides, one of the hallmarks of Alzheimer's disease. The intracellular location of A{beta} production--endosomes or the trans-Golgi network (TGN)--remains uncertain. We investigated the role of different postendocytic trafficking events in A{beta}40 production using an RNAi approach. Depletion of Hrs and Tsg101, acting early in the multivesicular body pathway, retained APP in early endosomes and reduced A{beta}40 production. Conversely, depletion of CHMP6 and VPS4, acting late in the pathway, rerouted endosomal APP to the TGN for enhanced APP processing. We found that VPS35 (retromer)-mediated APP recycling to the TGN was required for efficient A{beta}40 production. An interruption of the bidirectional trafficking of APP between the TGN and endosomes, particularly retromer-mediated retrieval of APP from early endosomes to the TGN, resulted in the accumulation of endocytosed APP in early endosomes with reduced APP processing. These data suggest that A{beta}40 is generated predominantly in the TGN, relying on an endocytosed pool of APP recycled from early endosomes to the TGN.
关键词：endocytosis ; endosomal sorting complexes required for transport pathway ; vesicular traffic ; protein sorting ; proteolytic processing
