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

doi:10.1038/s41467-020-16080-4

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

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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 language	English
Article number	2358
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16080-4
State	Published - 1 Dec 2020

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title = "N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer{\textquoteright}s disease",

abstract = "Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer{\textquoteright}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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AU - Lee, Ju Youn

AU - Han, Seung Hoon

AU - Park, Min Hee

AU - Song, Im Sook

AU - Choi, Min Koo

AU - Yu, Eunsoo

AU - Park, Cheol Min

AU - Kim, Hee Jin

AU - Kim, Seung Hyun

AU - Schuchman, Edward H.

AU - Jin, Hee Kyung

AU - Bae, Jae sung

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

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