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Retrograde transport of γ‐secretase from endosomes to the trans‐Golgi network regulates Aβ42 production
Author(s) -
Kanatsu Kunihiko,
Hori Yukiko,
Ebinuma Ihori,
Chiu Yung Wen,
Tomita Taisuke
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14477
Subject(s) - endosome , endocytosis , microbiology and biotechnology , amyloid precursor protein secretase , golgi apparatus , amyloid precursor protein , gamma secretase , secretory pathway , axoplasmic transport , alpha secretase , clathrin , intracellular , chemistry , neurodegeneration , biology , biochemistry , cell , alzheimer's disease , medicine , disease , endoplasmic reticulum
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.