lncRNA IGF2AS在绝经后认知功能减退中的作用及机制

Postmenopausal women are prone to cognitive decline and the mechanism is unknown. It has been found that long noncoding RNA IGF2AS can regulate the expression of brain-derived neurotrophic factor (BDNF) and affect the apoptosis of neurons, and IGF2 which can be regulated by IGF2AS is closely related to the progression of alzheimer's disease. In our previous study, the serum level of BDNF was decreased in women with cognitive decline. Compared with controls, the spatial memory ability was significantly improved in ovariectomized (OVX) rats with estrogen replacement therapy at the early postmenopausal stage, and the expression of BDNF in hippocampus increased. All above indicates the close relationship between BDNF and postmenopausal cognitive decline. IGF2AS may regulate the cognitive function after menopause via BDNF signaling pathway, while the study about IGF2AS function on postmenopausal cognitive decline is lack. In this study, the relationship between IGF2AS and postmenopausal cognitive decline and the alteration of BDNF/TrkB/Akt signaling pathway will be explored in vivo through the OVX-rats model. In addition, the primary culture of OVX-rats hippocampal neurons in vitro will be conducted, the alteration of neurons and BDNF signaling pathway will be observed under the conditions of IGF2AS overexpression and silent expression. It is hoped to explore the mechanism of the regulation of IGF2AS on postmenopausal cognitive decline and provide new targets for the prevention and treatment of cognitive impairment in postmenopausal women.

绝经妇女易发生认知功能减退，机制不明。研究已发现长链非编码RNA（lncRNA）IGF2AS可调节脑源性神经营养因子（BDNF）的表达，影响神经元的凋亡；其调节的IGF2与阿尔茨海默病的进展密切相关。我们的前期工作发现：轻度认知功能减退女性血清BDNF水平下降；去卵巢（OVX）大鼠早期雌激素治疗可改善视觉空间记忆能力，海马区BDNF表达增加，提示BDNF与绝经后认知功能减退密切相关。IGF2AS可能通过BDNF通路影响绝经后认知功能，而IGF2AS在绝经后认知功能减退中的研究尚缺乏。本研究拟：通过在体OVX大鼠绝经模型，观察IGF2AS与认知功能减退的关系及BDNF/TrkB/Akt通路的变化；通过体外OVX大鼠海马神经元原代培养，IGF2AS过表达或沉默表达时海马神经元结构及BDNF信号通路的变化，揭示IGF2AS对绝经后认知功能减退的调控机制，为绝经妇女认知障碍的防治提供新靶标。

绝经妇女易发生认知功能减退，机制不明。研究已发现长链非编码RNA（lncRNA）IGF2AS可调节脑源性神经营养因子（BDNF）的表达，影响神经元的凋亡；其调节的IGF2与阿尔茨海默病的进展密切相关。推测IGF2AS可能通过BDNF通路影响绝经后认知功能。本研究采用12周龄SD大鼠去卵巢建立绝经模型，设立假手术对照（sham）组、去卵巢（OVX）组和去卵巢后口服雌激素补充（ERT）组，饲养20周，通过Morris水迷宫测试评估认知功能的变化，观察海马神经元形态学变化，同时检测海马组织中IGF2AS和相关分子IGF2、BDNF、AKT和TrkB的基因和蛋白质表达水平，血清雌激素和BDNF水平；再通过体外小鼠皮质神经元原代培养，观察IGF2AS过表达或沉默表达时神经元结构及BDNF信号通路的变化。研究发现：与sham组相比，OVX组大鼠认知功能减退，海马树突及树突棘明显减少，髓鞘板层厚度增加，血管上皮细胞水肿，部分线粒体水肿，血清BDNF水平下降，海马组织中IGF2AS的基因表达上调，IGF2、TrkB、AKT和BDNF的基因表达下调，海马中相应的IGF2、TrkB和BDNF的蛋白产物显著减少，AKT差异无统计学意义；ERT组与sham组相比无显著差异。在体外小鼠皮质神经元的培养中，发现抑制了IGF2AS的表达时，IGF2、TrkB、BDNF的基因表达均上调，当IGF2AS过表达时，IGF2、TrkB、BDNF的基因表达均下调，IGF2及TrkB的蛋白表达与基因表达趋势一致。我们的研究提示去卵巢后大鼠认知功能下降，ERT有利于改善去卵巢大鼠的认知功能；IGF2AS可能通过调节IGF2及BDNF/TrkB/Akt信号通路影响雌激素下降引起的认知功能减退，结论有待进一步的验证。IGF2AS对绝经后认知功能减退的调控机制可能为绝经妇女认知障碍的防治提供新靶标。