Background

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism in neurodegenerative diseases, such as Alzheimer’s disease and vascular dementia. The orphan nuclear receptor TLX plays an important role in neural development, adult neurogenesis and cognition. The aim of this study was to investigate the neuroprotective effects of TLX on cognitive dysfunction, hippocampal neurogenesis and neuroinflammation in a rat model of CCH and to assess the possible mechanisms.

Methods

Permanent bilateral common carotid artery occlusion (2-VO) was used to establish a model of CCH. Stereotaxic injection of an adeno-associated virus vector expressing TLX was used to overexpress TLX in the hippocampus. Cognitive function was evaluated by the Morris Water Maze test. Immunofluorescent staining was used to assess hippocampal neurogenesis. The effects of overexpression of TLX on SIRT1 and inflammatory cytokines were analyzed with qRT-PCR and western blot.

Result

After 2-VO, CCH rats exhibited cognitive impairment and reduction of hippocampal TLX levels. Overexpression of TLX ameliorated cognitive impairments with increasing number of BrdU + cells and BrdU + NeuN + cells in DG. Furthermore, TLX rescued the reduced SIRT1 usually induced by CCH. Additionally, TLX also inhibited the expression of inflammatory cytokines such as NF-κB and IL-1β.

Conclusions

The present findings suggested that TLX exerted protective effects against cognitive deficits induced by CCH. The possible mechanisms of TLX may be through regulating the SIRT1/NF-κB pathway, promoting hippocampal neurogenesis and inhibiting the neuroinflammatory response.

中文翻译：

---

核受体TLX可能通过调节SIRT1/NF-κB通路改善慢性脑灌注不足的认知障碍

背景

慢性脑灌注不足（CCH）是神经退行性疾病（如阿尔茨海默病和血管性痴呆）中常见的病理生理机制。孤儿核受体 TLX 在神经发育、成人神经发生和认知中起着重要作用。本研究的目的是研究 TLX 对 CCH 大鼠模型中认知功能障碍、海马神经发生和神经炎症的神经保护作用，并评估可能的机制。

方法

采用永久性双侧颈总动脉闭塞（2-VO）建立CCH模型。立体定向注射表达 TLX 的腺相关病毒载体用于在海马中过表达 TLX。认知功能通过莫里斯水迷宫测试进行评估。免疫荧光染色用于评估海马神经发生。用 qRT-PCR 和蛋白质印迹分析 TLX 过表达对 SIRT1 和炎性细胞因子的影响。

结果

2-VO 后，CCH 大鼠表现出认知障碍和海马 TLX 水平降低。随着 DG 中 BrdU + 细胞和 BrdU + NeuN + 细胞数量的增加，TLX 的过表达改善了认知障碍。此外，TLX 挽救了通常由 CCH 诱导的减少的 SIRT1。此外，TLX 还抑制炎性细胞因子如 NF-κB 和 IL-1β 的表达。

结论

目前的研究结果表明，TLX 对 CCH 诱导的认知缺陷发挥了保护作用。TLX的可能机制可能是通过调节SIRT1/NF-κB通路，促进海马神经发生和抑制神经炎症反应。