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

Nat Commun. 2018 Apr 16;9(1):1479. doi: 10.1038/s41467-018-03674-2.

Ju Youn Lee ¹ ² ³, Seung Hoon Han ¹ ² ³, Min Hee Park ¹ ² ³, Bosung Baek ¹ ⁴, Im-Sook Song ⁵, Min-Koo Choi ⁶, Yoh Takuwa ⁷, Hoon Ryu ⁸ ⁹, Seung Hyun Kim ¹⁰, Xingxuan He ¹¹, Edward H Schuchman ¹¹, Jae-Sung Bae ¹² ¹³ ¹⁴, Hee Kyung Jin ¹⁵ ¹⁶

Affiliations

1 Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, 41566, South Korea.
2 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
3 Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, South Korea.
4 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, South Korea.
5 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, South Korea.
6 College of Pharmacy, Dankook University, Cheon-an, 31116, South Korea.
7 Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8640, Japan.
8 VA Boston Healthcare System, Department of Neurology and Boston University Alzheimer's Disease Centre, Boston University School of Medicine, Boston, MA, 02130, USA.
9 Centre for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
10 Department of Neurology, Hanyang University College of Medicine, Seoul, 04763, South Korea.
11 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12 Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, 41566, South Korea. jsbae@knu.ac.kr.
13 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. jsbae@knu.ac.kr.
14 Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, South Korea. jsbae@knu.ac.kr.
15 Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, 41566, South Korea. hkjin@knu.ac.kr.
16 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, South Korea. hkjin@knu.ac.kr.

PMID: 29662056 DOI: 10.1038/s41467-018-03674-2

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.

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