delta-COP modulates A beta peptide formation via retrograde trafficking of APP

作者：Bettayeb Karima; Chang Jerry C; Luo Wenjie; Aryal Suvekshya; Varotsis Dante; Randolph Lisa; Netzer William J; Greengard Paul^*; Flajolet Marc^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(19): 5412-5417.

DOI：10.1073/pnas.1604156113

• amyloid
• COPI
• retrograde transport
• Alzheimer
• trafficking

The components involved in cellular trafficking and protein recycling machinery that have been associated with increased Alzheimer's disease (AD) risk belong to the late secretory compartments for the most part. Here, we hypothesize that these late unavoidable events might be the consequence of earlier complications occurring while amyloid precursor protein (APP) is trafficking through the early secretory pathway. We investigated the relevance to AD of coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum (ER) retrograde transport and one of the very first trafficking steps. Using a complex set of imaging technologies, including inverse fluorescence recovery after photobleaching (iFRAP) and photoactivatable probes, coupled to biochemical experiments, we show that COPI subunit delta (delta-COP) affects the biology of APP, including its subcellular localization and cell surface expression, its trafficking, and its metabolism. These findings demonstrate the crucial role of delta-COP in APP metabolism and, consequently, the generation of amyloid-beta (A beta) peptide, providing previously nondescribed mechanistic explanations of the underlying events.

• 出版日期2016-5-10