N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease

Ju Youn Lee, Seung Hoon Han, Min Hee Park, Im Sook Song, Min Koo Choi, Eunsoo Yu, Cheol Min Park, Hee Jin Kim, Seung Hyun Kim, Edward H. Schuchman, Hee Kyung Jin, Jae sung Bae

Research output: Contribution to journalArticle

Abstract

Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer’s disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.

Original languageEnglish
Article number2358
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 2020 Dec 1

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    Lee, J. Y., Han, S. H., Park, M. H., Song, I. S., Choi, M. K., Yu, E., Park, C. M., Kim, H. J., Kim, S. H., Schuchman, E. H., Jin, H. K., & Bae, J. S. (2020). N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease. Nature Communications, 11(1), [2358]. https://doi.org/10.1038/s41467-020-16080-4