| RRC ID |
52671
|
| 著者 |
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.
|
| タイトル |
Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.
|
| ジャーナル |
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.
|
| 巻・号 |
9(1)
|
| ページ |
1479
|
| 公開日 |
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
|
| 引用数 |
18
|
| リソース情報 |
| ヒト・動物細胞 |
201B7(HPS0063) |
