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Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.


ABSTRACT: Although many reports have revealed the importance of defective microglia-mediated amyloid ? 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.

SUBMITTER: Lee JY 

PROVIDER: S-EPMC5902554 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.

Lee Ju Youn JY   Han Seung Hoon SH   Park Min Hee MH   Baek Bosung B   Song Im-Sook IS   Choi Min-Koo MK   Takuwa Yoh Y   Ryu Hoon H   Kim Seung Hyun SH   He Xingxuan X   Schuchman Edward H EH   Bae Jae-Sung JS   Jin Hee Kyung HK  

Nature communications 20180416 1


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  ...[more]

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