| First Author | Kanatsu K | Year | 2018 |
| Journal | J Neurochem | Volume | 147 |
| Issue | 1 | Pages | 110-123 |
| PubMed ID | 29851073 | Mgi Jnum | J:266127 |
| Mgi Id | MGI:6202510 | Doi | 10.1111/jnc.14477 |
| Citation | Kanatsu K, et al. (2018) Retrograde transport of gamma-secretase from endosomes to the trans-Golgi network regulates Abeta42 production. J Neurochem 147(1):110-123 |
| abstractText | The aberrant metabolism of amyloid-beta protein (Abeta) in the human brain has been implicated in the etiology of Alzheimer disease (AD). gamma-Secretase is the enzyme that generates various forms of Abeta, such as Abeta40 and Abeta42, the latter being an aggregation-prone toxic peptide that is involved in the pathogenesis of AD. Recently, we found that clathrin-mediated endocytosis of gamma-secretase affects the production and deposition of Abeta42 in vivo, suggesting that the membrane trafficking of gamma-secretase affects its enzymatic activity. However, the detailed intracellular trafficking pathway of gamma-secretase and its contribution to Abeta42 generation remain unclear. Here, we show that Retro-2, which inhibits the retrograde transport, elevated the Abeta42-generating activity both in cultured cells and mice brain. However, the result of in vitro gamma-secretase assay using a recombinant substrate suggested that Retro-2 did not elevate the intrinsic Abeta42-production activity of gamma-secretase. Immunocytochemistry and cell-surface biotinylation experiments revealed that gamma-secretase is recycled via the endosome-to-trans-Golgi network transport. In addition, gamma-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 Abeta42 levels and the Abeta42/(Abeta40 + Abeta42) ratio in secreted Abeta from cultured cells. Our results strongly suggest that the endosome-to-trans-Golgi network trafficking of gamma-secretase regulates its Abeta42 production activity. Modulation of this trafficking pathway might be a potential target for the development of Abeta42-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/. |
