Segregation of the membrane cargoes, BACE1 and amyloid precursor protein (APP) throughout the Golgi apparatus

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2022-03, Vol.23 (3), p.158-173
• Main Authors: Fourriere, Lou, Cho, Ellie Hyun‐Jung, Gleeson, Paul A.
• Format: Article
• Language: English
• Subjects: Airyscan microscopy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; amyloid precursor protein (APP); Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - metabolism; beta‐secretase 1 (BACE1); colocalization; Endoplasmic reticulum; Golgi Apparatus - metabolism; Golgi cells; HeLa Cells; Humans; Protein Transport - physiology; segregation; Transferrins; trans‐Golgi network (TGN); β-Amyloid; β-Site APP-cleaving enzyme 1
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12831

The intracellular trafficking of β‐site amyloid precursor protein (APP) cleaving enzyme (BACE1) and APP regulates amyloid‐β production. Our previous work demonstrated that newly synthesized BACE1 and APP are segregated into distinct trafficking pathways from the trans‐Golgi network (TGN), and that alterations in their trafficking lead to an increase in Aβ production in non‐neuronal and neuronal cells. However, it is not known whether BACE1 and APP are transported through the Golgi stacks together and sorted at the TGN or segregated prior to arrival at the TGN. To address this question, we have used high‐resolution Airyscan technology followed by Huygens deconvolution to quantify the overlap of BACE1 and APP in Golgi subcompartments in HeLa cells and primary neurons. Here, we show that APP and BACE1 are segregated, on exit from the endoplasmic reticulum and in the cis‐Golgi and throughout the Golgi stack. In contrast, the transferrin receptor, which exits the TGN in AP‐1 mediated transport carriers as for BACE1, colocalizes with BACE1, but not APP, throughout the Golgi stack. The segregation of APP and BACE1 is independent of the Golgi ribbon structure and the cytoplasmic domain of the cargo. Overall, our findings reveal the segregation of different membrane cargoes early in the secretory pathway, a finding relevant to the regulation of APP processing events. Amyloid precursor protein (APP) and the β‐secretase, BACE1, are sorted into different post‐Golgi transport pathways. Here, we investigated the partitioning of APP and BACE1 along the secretory pathway. Using super‐resolution microscopy, we show that APP and BACE1 are segregated in the cis‐Golgi and throughout the Golgi stack in HeLa cells and primary neurons, whereas, the transferrin receptor, colocalizes with BACE1 but not APP. These findings reveal segregation of membrane cargoes early in the secretory pathway, which we propose limits APP processing.