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

摘要

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. Conversely, TPT ‐260, which enhances the trafficking function of retromers, lowered Aβ42 levels and the Aβ42/(Aβ40?+?Aβ42) ratio in secreted Aβ from cultured cells. Our results strongly suggest that the endosome‐to‐ trans ‐Golgi network trafficking of γ‐secretase regulates its Aβ42 production activity. Modulation of this trafficking pathway might be a potential target for the development of Aβ42‐lowering AD therapeutics. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/