COPI-mediated retrograde transport is required for efficient γ-secretase cleavage of the amyloid precursor protein

Sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases results in the production of β-amyloid peptide, which is a key determinant in Alzheimer’s disease. Since several putative locations for γ-secretase cleavage have been identified along the secretory pathway, trafficking of APP may be of importance for β-amyloid peptide production. Here we have studied the role of retrograde transport in APP processing. We found that APP interacts with the β subunit of the coatomer protein I (COPI) complex, which is involved in retrograde transport. In line with a role of retrograde trafficking in APP transport, inhibition of COPI-dependent transport altered APP trafficking, decreased APP cell surface expression, and coincided with a profound reduction in γ-secretase cleavage. These results suggest that COPI-dependent retrograde transport is important for APP processing and influences production of β-amyloid peptide.