N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer\u2019s disease

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

doi:10.1038/s41467-020-16080-4

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.

Highlights

Sphingosine kinase[1] (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase[2] (COX2) in neurons in a model of Alzheimer’s disease (AD)
These results indicated that N-acetyl sphingosine (N-AS), as an intermediate for Sphingosine kinase1 (SphK1)-mediated COX2 acetylation, had high binding affinity and induced high-level acetylation of COX2
N-AS generation, N-AS-mediated acetyl-serine 565 (S565) COX2 was observed in both neurons and microglia, but not in astrocytes. These studies confirmed that in the presence of amyloid β (Aβ), the levels of N-AS-acetylated COX2 were decreased in both neurons and microglia (Fig. 3b, c). These results indicated that N-AS was generated, and acetylated S565 of COX2 in neuron and microglia, which was abrogated with Aβ treatment

Summary

Introduction

Sphingosine kinase[1] (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase[2] (COX2) in neurons in a model of Alzheimer’s disease (AD). Amyloid β (Aβ)-treated human microglia showed reduction of N-AS generation, and N-AS treatment of these human cells improved SPM production and phagocytosis capacity as well Overall, these results reveal a biosynthetic mechanism and function of N-AS, which leads to S565 acetylation of COX2 and production of SPMs. Overall, these results reveal a biosynthetic mechanism and function of N-AS, which leads to S565 acetylation of COX2 and production of SPMs They reveal the relation of N-AS with microglial regulation in AD pathogenesis, and suggest a potential therapy for neuroinflammatory diseases, such as AD, using N-AS or related derivatives that could be evaluated in the future

Methods

Results

Conclusion