δ-COP modulates Aβ peptide formation via retrograde trafficking of APP.
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 δ (δ-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 δ-COP in APP metabolism and, consequently, the generation of amyloid-β (Aβ) peptide, providing previously nondescribed mechanistic explanations of the underlying events.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Karima
K
Bettayeb
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Jerry C
JC
Chang
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Wenjie
W
Luo
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Suvekshya
S
Aryal
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Dante
D
Varotsis
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Lisa
L
Randolph
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
William J
WJ
Netzer
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 flajolm@rockefeller.edu greengard@rockefeller.edu.
Paul
P
Greengard
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 flajolm@rockefeller.edu greengard@rockefeller.edu.
Marc
M
Flajolet
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D020756:Coatomer Protein / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020756:Coatomer Protein
Alzheimer; COPI; amyloid; retrograde transport; trafficking