RRC ID 52671
Author Lee JY, Han SH, Park MH, Baek B, Song IS, Choi MK, Takuwa Y, Ryu H, Kim SH, He X, Schuchman EH, Bae JS, Jin HK.
Title Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.
Journal Nat Commun
Abstract 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.
Volume 9(1)
Pages 1479
Published 2018-4-16
DOI 10.1038/s41467-018-03674-2
PII 10.1038/s41467-018-03674-2
PMID 29662056
PMC PMC5902554
MeSH Acetyl Coenzyme A / metabolism* Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Alzheimer Disease / enzymology* Alzheimer Disease / genetics Alzheimer Disease / pathology Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism Animals Brain / enzymology Brain / pathology Cyclooxygenase 2 / genetics Cyclooxygenase 2 / metabolism* Disease Models, Animal Humans Lipoxins / metabolism Male Mice Mice, Transgenic Microglia / enzymology* Microglia / pathology Neurons / enzymology* Neurons / pathology Phagocytosis Presenilin-1 / genetics Presenilin-1 / metabolism Serine / metabolism Transgenes
IF 12.121
Times Cited 18
Human and Animal Cells 201B7(HPS0063)