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MBC in Press, published online ahead of print October 24, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0465

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Submitted on May 18, 2007
Revised on September 4, 2007
Accepted on October 12, 2007

Mint3/X11{gamma} Is an Arf-dependent Adaptor that Regulates the Traffic of the Alzheimer’s Precursor Protein from the TGN

Punya Shrivastava-Ranjan,*{dagger} Victor Faundez,{dagger}{ddagger} Guofu Fang,{dagger}{sect} Howard Rees,{dagger}{sect} James J. Lah,{dagger}{sect} Allan I. Levey,{dagger}{sect} and Richard A. Kahn*{dagger}

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

Monitoring Editor: Vivek Malhotra

{beta}-amyloid peptides (A{beta}) are the major component of plaques in brains of Alzheimer’s patients and are derived from the proteolytic processing of the {beta}-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated and 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 show 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 TGN to the plasma membrane include the observations that depletion of Mint3 by 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 {beta}-amyloid peptide, A{beta}1–40. Taken together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic.

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






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