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PMID:29662056

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Citation

Lee, JY, Han, SH, Park, MH, Baek, B, Song, IS, Choi, MK, Takuwa, Y, Ryu, H, Kim, SH, He, X, Schuchman, EH, Bae, JS and Jin, HK (2018) Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease. Nat Commun 9:1479

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.

Links

PubMed PMC5902554 Online version:10.1038/s41467-018-03674-2

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SPHK1

enables

GO:0016407: acetyltransferase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SPHK1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SPHK1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SPHK1

involved_in

GO:0006473: protein acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPHK1

involved_in

GO:0050764: regulation of phagocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPHK1

involved_in

GO:1903978: regulation of microglial cell activation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPHK1

involved_in

GO:0150077: regulation of neuroinflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PGH2

involved_in

GO:0150077: regulation of neuroinflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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