Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease

Ju Youn Lee, Seung Hoon Han, Min Hee Park, Bosung Baek, Im-Sook Song, Min-Koo Choi, Yoh Takuwa, Hoon Ryu, Seung Hyun Kim, Xingxuan He, Edward H. Schuchman, Jae-Sung Bae () and Hee Kyung Jin ()
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Ju Youn Lee: Kyungpook National University
Seung Hoon Han: Kyungpook National University
Min Hee Park: Kyungpook National University
Bosung Baek: Kyungpook National University
Im-Sook Song: Kyungpook National University
Min-Koo Choi: Dankook University
Yoh Takuwa: Kanazawa University School of Medicine
Hoon Ryu: Boston University School of Medicine
Seung Hyun Kim: Hanyang University College of Medicine
Xingxuan He: Icahn School of Medicine at Mount Sinai
Edward H. Schuchman: Icahn School of Medicine at Mount Sinai
Jae-Sung Bae: Kyungpook National University
Hee Kyung Jin: Kyungpook National University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Although many reports have revealed the importance of defective microglia-mediated amyloid β phagocytosis in Alzheimer’s disease (AD), the underlying mechanism remains to be explored. Here we demonstrate that neurons in the brains of patients with AD and AD mice show reduction of sphingosine kinase1 (SphK1), leading to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized proresolving mediators (SPMs). Elevation of SphK1 increased SPMs secretion, especially 15-R-Lipoxin A4, by promoting acetylation of serine residue 565 (S565) of cyclooxygenase2 (COX2) using acetyl-CoA, resulting in improvement of AD-like pathology in APP/PS1 mice. In contrast, conditional SphK1 deficiency in neurons reduced SPMs secretion and abnormal phagocytosis similar to AD. Together, these results uncover a novel mechanism of SphK1 pathogenesis in AD, in which impaired SPMs secretion leads to defective microglial phagocytosis, and suggests that SphK1 in neurons has acetyl-CoA-dependent cytoplasmic acetyltransferase activity towards COX2.

Date: 2018
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DOI: 10.1038/s41467-018-03674-2

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