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

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Listed:
  • Ju Youn Lee

    (Kyungpook National University
    Kyungpook National University
    Kyungpook National University)

  • Seung Hoon Han

    (Kyungpook National University
    Kyungpook National University
    Kyungpook National University)

  • Min Hee Park

    (Kyungpook National University
    Kyungpook National University
    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
    Kyungpook National University)

  • Jae-sung Bae

    (Kyungpook National University
    Kyungpook National University
    Kyungpook National University)

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.

Suggested Citation

  • 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, 2020. "N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16080-4
    DOI: 10.1038/s41467-020-16080-4
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