神经限制性沉默因子REST在大脑衰老向退行性变转化中的作用机制研究

Alzheimer’s disease is the most common form of neurodegeneration. How the brain changes from aging to neurodegeneration remains elusive. Our preliminary studies have shown that RE1 silencing transcription factor (REST) is elevated with aging in normal mice; however, both mRNA and protein levels of REST are reduced with aging in AD mice. REST is a critical transcriptional factor involved in neuronal development as well as neurogenesis in adults. Thus we hypothesized that dysregulations of REST in aging in AD induced impairments in neurogenesis, which contributed to the transition from normal aging to neurodegeneration. To address this, we would knockdown REST expression using a Tet-on3G AAV system in different ages of Nestin-EGFP reporter mice. Neurogenesis and neurobehavioral tests would be conducted to reflect the effect of REST downregulation in neurodegeneration. Concormitantly, REST expression in AD mice at different ages would be upregulated by a Tet-on3G AAV system. And neurogenesis, AD pathogenesis as well as memory tests would be conducted to reflect the results of REST upregulation in AD mice on neurodegeneration. The target genes of REST in neurogenesis would be determined by 2nd generation sequencing conducted using neural stem cells at different ages and different expression levels of REST. The target genes would be verified in neurogenesis in vitro and in vivo. The elucidation of REST and neurogenesis in mice at different ages will provide the new understandings of brain aging and neurodegeneration.

阿尔茨海默病（AD）是一种老年人最常见的神经系统退行性疾病，AD已成为严重危害我国老年人群健康的重大疾病之一，研究大脑衰老向退行性变的机制意义重大。在初步试验中我们使用AD模型小鼠的研究结果发现在正常衰老的小鼠大脑内神经元限制性沉默因子NRSF/REST表达上调，但是在AD模型小鼠脑内随着老龄化REST表达反而下调，由于REST与神经再生密切相关，因此我们假设REST引起的神经再生障碍引起了大脑衰老向退行变的转变，为了验证这一假设，我们将在不同年龄的正常小鼠大脑内敲低REST表达以及AD模型小鼠大脑内升高REST的表达，研究衰老过程中REST表达变化对大脑海马神经细胞再生以及神经退行性变的影响，通过对比不同年龄神经干细胞转录组水平的变化明确REST参与大脑衰老向退行性变转化的分子机制。此研究将进一步明确神经再生障碍在大脑衰老和退行变中的意义，并为积极发展AD的治疗提供新的理论基础。

阿尔茨海默氏症(AD) 是导致老年人痴呆的主要原因。本项目主要研究REST表达变化对大脑认知功能的影响。REST在人类正常老化的大脑皮层和海马神经元中表达升高，但在中度认知障碍和AD 患者大脑中表达减少，而且其在细胞中的定位也发生了变化。在正常衰老的大脑神经元中REST大部分位于细胞核，而其在痴呆症患者大脑神经元中多位于细胞质，REST表达水平以及定位的改变提示 REST在大脑认知功能中可能存在重要作用。先前研究提示，REST转录活性可通过NOTCH信号通路调节。NOTCH基因家族编码一类高度保守的细胞表面跨膜受体蛋白，通过相邻细胞间的相互作用调节细胞的增殖、分化、凋亡等过程。与NOTCH相关的疾病中较为常见的是NOTCH3基因突变所致的伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)。CADASIL的主要临床特征是反复发作的皮质下脑卒中和进行性认知损害经典。我们研究发现，REST表达受NOTCH信号通路调控，我们继续探讨了REST在大脑衰老向退行性转化过程中的功能及作用机制和REST-NOTCH3 axis在认知功能损害中相互作用的分子机制研究。