Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)

The presence of neuritic plaques containing aggregated amyloid-beta (A beta) peptides in the brain parenchyma is a pathological hallmark of Alzheimer disease (AD). A beta is generated by sequential cleavage of the amyloid beta precursor protein (APP) by beta- and gamma-secretase, respectively. As APP processing to A beta requires transport through the secretory pathway, trafficking of the substrate and access to the secretases are key factors that can influence A beta production (Thinakaran, G., and Koo, E. H. (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619). Here, we report that retention in endoplasmic reticulum 1 (RER1) associates with gamma-secretase in early secretory compartments and regulates the intracellular trafficking of gamma-secretase. RER1 overexpression decreases both gamma-secretase localization on the cell surface and A beta secretion and conversely RER1 knockdown increases the level of cell surface gamma-secretase and increases A beta secretion. Furthermore, we find that increased RER1 levels decrease mature APP and increase immature APP, resulting in less surface accumulation of APP. These data show that RER1 influences the trafficking and localization of both gamma-secretase and APP, thereby regulating the production and secretion of A beta peptides.