المؤلفون: Hee Jin Kim, Seung Hyun Kim, Cheol-Min Park, Jae-sung Bae, Ju Youn Lee, Min-Koo Choi, Min Hee Park, Eunsoo Yu, Hee Kyung Jin, Edward H. Schuchman, Seung Hoon Han, Im-Sook Song

المصدر: Nature Communications, Vol 11, Iss 1, Pp 1-19 (2020)
Nature Communications

مصطلحات موضوعية: 0301 basic medicine, Male, Neuroimmunology, Anti-Inflammatory Agents, General Physics and Astronomy, Serine, chemistry.chemical_compound, Mice, 0302 clinical medicine, Sphingosine, lcsh:Science, Neurons, Multidisciplinary, Microglia, Brain, food and beverages, Acetylation, Alzheimer's disease, Recombinant Proteins, Phosphotransferases (Alcohol Group Acceptor), medicine.anatomical_structure, Acetyltransferase, medicine.symptom, Phagocytosis, Transgene, Science, Primary Cell Culture, Inflammation, Mice, Transgenic, macromolecular substances, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Acetyl Coenzyme A, Alzheimer Disease, Memory, medicine, Presenilin-1, Animals, Humans, Neuroinflammation, General Chemistry, Disease Models, Animal, 030104 developmental biology, chemistry, nervous system, Cyclooxygenase 2, Mutagenesis, lcsh:Q, Neuroscience, 030217 neurology & neurosurgery

الوصف: 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.
Neuronal sphingosine kinase 1 (SphK1) acetylates COX2 which is needed for microglial phagocytosis activity, and release of pro-resolving mediators (SPMs) from neurons. Here the authors examine how SphK1-mediates COX2 acetylation, and how this leads to increased secretion of SPMs from neurons in the context of Alzheimer’s disease models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::782a4eb0726efb66ab89568cfe37f061Test
https://doaj.org/article/3035df8592594ac98f3be370c56a59d8Test

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

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

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ea500e15b6f06ae89518c0f2ea28e85Test
https://doi.org/10.1038/s41467-018-03674-2Test