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Ligand for translocator protein increases hippocampal expression of glial Abeta scavenger receptors and reduces Abeta in male mice & rats
https://repo.qst.go.jp/records/65089
https://repo.qst.go.jp/records/65089a46c598d-77c8-49aa-910b-58f5f0af7e1a
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2013-07-31 | |||||
| タイトル | ||||||
| タイトル | Ligand for translocator protein increases hippocampal expression of glial Abeta scavenger receptors and reduces Abeta in male mice & rats | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Barron, Anna
× Barron, Anna× Tokunaga, Masaki× Ki, Hin× Suhara, Tetsuya× Higuchi, Makoto× Ｂａｒｒｏｎ Ａｎｎａ× 徳永 正希× 季 斌× 須原 哲也× 樋口 真人 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Background Translocator protein (TSPO) is a multi-functional mitochondrial transmembrane protein primarily localised in steroid-producing tissues, including the brain. TSPO ligands elicit pleiotropic neuroprotective and cognitive benefits, mechanistically linked to the regulation of steroid synthesis and gliosis. Our recent findings in 3xTgAD mice demonstrate that TSPO ligands not only reduce development of Abeta neuropathology in young mice, but also reverse pathology in aged mice, suggesting TSPO ligands may promote Abeta clearance. Since glia-mediated Abeta phagocytosis and degradation is an important mechanism of brain Abeta clearance, we investigated the effect of a TSPO ligand on markers of glial function and expression of glial Abeta-scavenging receptors. Methods Effects of the TSPO ligands, Ro5-4864 and PK-11195, on brain Abeta levels in mice were assessed. The dose dependent effects of the most effective ligand, Ro5-4864, were compared with the anti-amyloidogenic neuroactive steroid, testosterone, in rats. Abeta levels were assessed by ELISA and hippocampal mRNA expression of markers of glial function (glial fibrillary acidic protein; GFAP; major histopatability complex II; MHC II; interleukin-1beta; IL-1beta; tumor necrosis factor-alpha, TNF-alpha) and glial Abeta scavenger receptors (scavenger receptor-A1, SR-A1; scavenger receptor-B1, SR-B1) were assessed by PCR. Results Ro5-4864 reduced Abeta-40 more effectively than PK-11195, while combined Ro5-4864 + PK-11195 had an additive anti-amyloidogenic effect. In rats, Ro5-4864 dose-dependently reduced Abeta-40 levels and was equally effective as testosterone. In Ro5-4864 treated rats, reduced Abeta levels were associated with elevated expression of GFAP, MHC-II, and glial Abeta scavenger receptors; although levels of the pro-inflammatory cytokines, IL-1beta and TNFalpha, were unaltered. In contrast, testosterone had an anti-inflammatory effect, reducing levels of GFAP, MHC-II, IL-1beta and TNF-alpha, without altering expression of glial scavenger receptors. Conclusions The TSPO ligand Ro5-4864 may promote trophic glial activity, including increasing Abeta phagocytic capacity in the absence of detrimental proinflammatory cytokine production. Since glial TSPO is upregulated in the most severely affected regions of the Alzheimer`s brain, TSPO ligands may selectively target regions most affected by the disease. Many new generation, safe TSPO ligands have been developed for in vivo imaging in humans, however our findings suggest these ligands may also have a therapeutic potential for the treatment of Alzheimer`s. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | The Alzheimer's Association International Conference 2013 | |||||
| 発表年月日 | ||||||
| 日付 | 2013-07-18 | |||||
| 日付タイプ | Issued | |||||
