A novel sorting nexin modulates endocytic trafficking and α-secretase cleavage of the amyloid precursor protein

Susanne Schöbel, Stephanie Neumann, Maren Hertweck, Bastian Dislich, Peer Hendrik Kuhn, Elisabeth Kremmer, Brian Seed, Ralf Baumeister, Christian Haass, Stefan F. Lichtenthaler

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases α- and β-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid β peptide (Aβ). β-Secretase catalyzes the first step in Aβ generation, whereas α-secretase cleaves within the Aβ domain, prevents Aβ generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP α-secretase cleavage and Aβ generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP α-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP α-secretase cleavage 4-fold but surprisingly had little effect on β-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where α-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP α-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP α-secretase cleavage.

Original languageEnglish
Pages (from-to)14257-14268
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number21
DOIs
StatePublished - 23 May 2008
Externally publishedYes

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