論文 - 詳細
| RRC ID | 58033 |
|---|---|
| 著者 | Ni J, Wu Z, Meng J, Saito T, Saido TC, Qing H, Nakanishi H. |
| タイトル | An impaired intrinsic microglial clock system induces neuroinflammatory alterations in the early stage of amyloid precursor protein knock-in mouse brain. |
| ジャーナル | J Neuroinflammation |
| Abstract |
BACKGROUND:Disturbances in clock genes affect almost all patients with Alzheimer's disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. METHODS:In this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests. RESULTS:CLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice. CONCLUSION:Clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD. |
| 巻・号 | 16(1) |
| ページ | 173 |
| 公開日 | 2019-8-30 |
| DOI | 10.1186/s12974-019-1562-9 |
| PII | 10.1186/s12974-019-1562-9 |
| PMID | 31470863 |
| PMC | PMC6716829 |
| MeSH | Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism* Animals Brain / drug effects Brain / metabolism* CLOCK Proteins / antagonists & inhibitors CLOCK Proteins / genetics CLOCK Proteins / metabolism* Gene Knock-In Techniques / methods* Inflammation / genetics Inflammation / metabolism Inflammation Mediators / agonists Inflammation Mediators / metabolism* Locomotion / drug effects Locomotion / physiology Mice Mice, Inbred C57BL Mice, Transgenic Microglia / drug effects Microglia / metabolism* Pyrrolidines / toxicity Thiophenes / toxicity |
| IF | 5.793 |
| 引用数 | 2 |
| リソース情報 | |
| ヒト・動物細胞 | MG6(RCB2403) |