COPI-mediated retrograde transport is required for efficient gamma-secretase cleavage of the amyloid precursor protein.
Sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in the production of beta-amyloid peptide, which is a key determinant in Alzheimer's disease. Since several putative locations for gamma-secretase cleavage have been identified along the secretory pathway, trafficking of APP may be of importance for beta-amyloid peptide production. Here we have studied the role of retrograde transport in APP processing. We found that APP interacts with the beta 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 gamma-secretase cleavage. These results suggest that COPI-dependent retrograde transport is important for APP processing and influences production of beta-amyloid peptide.
Selivanova
Alexandra
A
Department of Neurobiology, Caring Sciences and Society (NVS), KI Alzheimer Disease Research Center, Karolinska Institutet, Novum 5th floor, S-141 57 Stockholm, Sweden. Alexandra.Selivanova@ki.se
Winblad
Bengt
B
Farmery
Mark R
MR
Dantuma
Nico P
NP
Ankarcrona
Maria
M
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D020755:Coat Protein Complex I / Q000378:metabolism*; D006224:Cricetinae; D006801:Humans; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
D016564:Amyloid beta-Protein Precursor; D020755:Coat Protein Complex I; D053829:Amyloid Precursor Protein Secretases