한빛사 논문
Ju Youn Lee1,2,3,10, Seung Hoon Han1,2,3,10, Min Hee Park1,2,3, Im-Sook Song4, Min-Koo Choi5, Eunsoo Yu6, Cheol-Min Park6, Hee-Jin Kim7, Seung Hyun Kim7, Edward H. Schuchman8, Hee Kyung Jin1,9,* & Jae-sung Bae1,2,3,*
1KNU Alzheimer’s Disease Research Institute, Kyungpook National University, Daegu 41566, South Korea.
2Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, South Korea.
3Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, South Korea.
4College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, South Korea.
5College of Pharmacy, Dankook University, Cheon-an 31116, South Korea.
6Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, South Korea.
7Department of Neurology, Hanyang University College of Medicine, Seoul 04763, South Korea.
8Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea.
10These authors contributed equally: Ju Youn Lee, Seung Hoon Han
*Corresponding author
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.
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