Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease
| العنوان: | Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease |
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| المؤلفون: | Jae-sung Bae, Seung Hyun Kim, Hoon Ryu, Ju Youn Lee, Hee Kyung Jin, Xingxuan He, Im-Sook Song, Min‑Koo Choi, Seung Hoon Han, Bosung Baek, Yoh Takuwa, Edward H. Schuchman, Min Hee Park |
| المصدر: | Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) Nature Communications |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Science, Phagocytosis, Transgene, General Physics and Astronomy, Mice, Transgenic, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Presenilin, Pathogenesis, Amyloid beta-Protein Precursor, Mice, 03 medical and health sciences, chemistry.chemical_compound, Acetyl Coenzyme A, Alzheimer Disease, Presenilin-1, Serine, medicine, Animals, Humans, Secretion, Transgenes, lcsh:Science, Adaptor Proteins, Signal Transducing, Neurons, Multidisciplinary, Sphingosine, Microglia, Brain, General Chemistry, medicine.disease, Cell biology, Lipoxins, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, chemistry, Cyclooxygenase 2, lcsh:Q, Alzheimer's disease |
| الوصف: | 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. Sphingosine kinase (SphK) converts sphingosine into lipids, and is implicated in inflammation. Here the authors show that SphK1 functions as an acetyltransferase, regulates microglial phagocytosis and is reduced in a model of Alzheimer’s Disease, such that its restoration ameliorates pathology |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ea500e15b6f06ae89518c0f2ea28e85Test https://doi.org/10.1038/s41467-018-03674-2Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2ea500e15b6f06ae89518c0f2ea28e85 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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