WEKO3
アイテム
TRANSLOCATOR PROTEIN AS A THERAPEUTIC TARGET FOR ALZHEIMER`S DISEASE
https://repo.qst.go.jp/records/65686
https://repo.qst.go.jp/records/656861249b9f6-eaa7-4791-8a88-b4b053463a6c
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2015-03-17 | |||||
| タイトル | ||||||
| タイトル | TRANSLOCATOR PROTEIN AS A THERAPEUTIC TARGET FOR ALZHEIMER`S DISEASE | |||||
| 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× Asih, Prita× Ji, Bin× Suhara, Tetsuya× Christian, Pike× Andrew, Katsifis× Ralph N, Martins× Higuchi, Makoto× Barron, Anna× Asih, Prita× Ji, Bin× Suhara, Tetsuya× Higuchi, Makoto |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Translocator protein (TSPO) is a multi-functional mitochondrial transmembrane protein primarily localized in steroid-producing tissues such as the brain. TSPO ligands elicit pleiotropic neuroprotective and cognitive benefits, mechanistically linked to the regulation of steroid synthesis. Our recent findings demonstrate that TSPO ligands promote neurosteroidogenesis, reduce Aβ neuropathology and neuroinflammation, and improve functional outcomes in the 3xTgAD Alzheimer`s disease (AD) mouse model (1). To evaluate the role of steroid biosynthesis in the mechanism(s) by which TSPO ligands improve AD-related neuropathological and behavioral outcomes, wild type mice were treated with the TSPO ligand Ro5-4864, combined with pre-administration of the steroid biosynthesis inhibitor, aminoglutethimide (AG). AG is a well characterized pharmacological inhibitor of the side-chain cleaving enzyme, P450scc, which is responsible for the conversion of cholesterol to pregnenolone, the precursor to all other neurosteroids. The anxiolytic and recognition memory benefits of Ro5-4864 were completely ablated by inhibition of steroid biosynthesis with AG. In contrast, the anti-amyloidogenic effects of Ro5-4864 were not blocked by co-administration of AG, suggesting TSPO-mediated reductions in AD-related neuropathology are largely independent of neurosteroidogenesis. These findings suggest the pleiotropic neuroprotective benefits of TSPO ligands may be mediated by separate mechanisms, with the rapid behavioral benefits attributable to TSPO-stimulated steroid biosynthesis while potential disease-modifying effects on AD-related pathology may be mediated by direct effects on glial function, altered mitochondrial function or cholesterol homeostasis. Therefore, TSPO ligands may offer both preventative and symptomatic therapeutic windows of opportunity. However, first generation TSPO ligands have low specificity, solubility and blood-brain barrier penetration, and consequently are unsuitable for clinical development. Numerous selective, high affinity, novel TSPO ligands have been developed for use as neuroimaging agents, which may also be useful as therapeutic compounds against AD. To identify novel candidate TSPO ligands that can induce steroidogenesis, we characterized the acute effects of three second generation TSPO ligands on learning and memory, anxiety, and depression related behaviors in wild-type mice, confirming their specificity in TSPO-knock out mice. Using competitive positron emission tomography, we evaluated the biodistribution and kinetic characteristics of ligand uptake, metabolism and TSPO receptor occupancy in order to identify ligands with desirable pharmacokinetic outcomes. Second generation TSPO ligands are promising candidates for the development of a targeted alternative to conventional hormone therapy, and may offer both disease modifying and symptomatic treatment opportunities with a favorable side-effect profile, including absence of sedation tolerance, withdrawal symptoms or motor impairment. | |||||
| 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 | International Meeting on Steroids and Nervous System | |||||
| 発表年月日 | ||||||
| 日付 | 2015-02-17 | |||||
| 日付タイプ | Issued | |||||
