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 () and Jae-sung Bae ()
Additional contact information
Ju Youn Lee: Kyungpook National University
Seung Hoon Han: Kyungpook National University
Min Hee Park: Kyungpook National University
Im-Sook Song: Kyungpook National University
Min-Koo Choi: Dankook University
Eunsoo Yu: Ulsan National Institute of Science and Technology (UNIST)
Cheol-Min Park: Ulsan National Institute of Science and Technology (UNIST)
Hee-Jin Kim: Hanyang University College of Medicine
Seung Hyun Kim: Hanyang University College of Medicine
Edward H. Schuchman: Icahn School of Medicine at Mount Sinai
Hee Kyung Jin: Kyungpook National University
Jae-sung Bae: Kyungpook National University

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16080-4

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