Retrograde transport of γ-secretase from endosomes to the trans-Golgi network regulates Aβ42 production

Journal of Neurochemistry
Kunihiko KanatsuTaisuke Tomita

Abstract

The aberrant metabolism of amyloid-β protein (Aβ) in the human brain has been implicated in the etiology of Alzheimer disease (AD). γ-Secretase is the enzyme that generates various forms of Aβ, such as Aβ40 and Aβ42, the latter being an aggregation-prone toxic peptide that is involved in the pathogenesis of AD. Recently, we found that clathrin-mediated endocytosis of γ-secretase affects the production and deposition of Aβ42 in vivo, suggesting that the membrane trafficking of γ-secretase affects its enzymatic activity. However, the detailed intracellular trafficking pathway of γ-secretase and its contribution to Aβ42 generation remain unclear. Here, we show that Retro-2, which inhibits the retrograde transport, elevated the Aβ42-generating activity both in cultured cells and mice brain. However, the result of in vitro γ-secretase assay using a recombinant substrate suggested that Retro-2 did not elevate the intrinsic Aβ42-production activity of γ-secretase. Immunocytochemistry and cell-surface biotinylation experiments revealed that γ-secretase is recycled via the endosome-to-trans-Golgi network transport. In addition, γ-secretase is retrogradely transported by syntaxin 5/6, known as targets of Retro-2, independent pathway. Con...Continue Reading

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Citations

Aug 3, 2018·Journal of Neurochemistry·Barbara Schweitzer, Jörg B Schulz
Apr 21, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yung Wen ChiuTaisuke Tomita

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