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

Nature communications (2020-05-14)
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
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.

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