N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer's disease.
Ju Youn LeeSeung Hoon HanMin Hee ParkIm-Sook SongMin-Koo ChoiEunsoo YuCheol-Min ParkHee-Jin KimSeung Hyun KimEdward H SchuchmanHee Kyung JinJae-Sung BaePublished in: Nature communications (2020)
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.
Keyphrases
- inflammatory response
- neuropathic pain
- mouse model
- lipopolysaccharide induced
- lps induced
- cognitive decline
- palliative care
- traumatic brain injury
- oxidative stress
- spinal cord injury
- fatty acid
- protein kinase
- working memory
- transcription factor
- skeletal muscle
- nitric oxide
- tyrosine kinase
- brain injury
- metabolic syndrome
- mild cognitive impairment
- high fat diet induced
- adipose tissue
- smoking cessation
- cerebral ischemia