QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 1, 51-64, January 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E07-05-0465v1 19/1/51    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shrivastava-Ranjan, P. Articles by Kahn, R. A. PubMed PubMed Citation Articles by Shrivastava-Ranjan, P. Articles by Kahn, R. A.

Mint3/X11 Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from the Trans-Golgi Network

Punya Shrivastava-Ranjan^*,, Victor Faundez^,, Guofu Fang^,, Howard Rees^,, James J. Lah^,, Allan I. Levey^,, and Richard A. Kahn^*,

Departments of *Biochemistry, Cell Biology, and Neurology and the Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322-3050

Submitted May 18, 2007; Revised September 4, 2007; Accepted October 12, 2007
Monitoring Editor: Vivek Malhotra

β-Amyloid peptides (Aβ) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the β-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic β-amyloid peptide, Aβ_1-40. Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic.

¹ APP is alternatively spliced and can be expressed in three different lengths of 695, 751, and 770 residues. Although the shortest form migrates well below the other two, the 751 and 770 proteins are most often found to run together. We do not distinguish between the 751 and 770 forms here.

Address correspondence to: Richard A. Kahn (rkahn{at}emory.edu).