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- Title
N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer's disease.
- Authors
Lee, Ju Youn; Han, Seung Hoon; Park, Min Hee; Song, Im-Sook; Choi, Min-Koo; Yu, Eunsoo; Park, Cheol-Min; Kim, Hee-Jin; Kim, Seung Hyun; Schuchman, Edward H.; Jin, Hee Kyung; Bae, Jae-sung
- 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. 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.
- Subjects
MICROGLIA; ALZHEIMER'S disease; SPHINGOSINE kinase; PHAGOCYTOSIS; ACETYLCOENZYME A; ACETYLTRANSFERASES
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-16080-4