Wang Yanfang, Liu Yingxin, Zhao Ziwei, Wu Xinyu, Lin Jiabin, Li Yufei, Yan Wei, Wu Yi, Shi Yanfei, Wu Xindi, Xue Ying, He Jiaqian, Liu Shuqi, Zhang Xiaonan, Xu Hong, Tang Yiyuan, Yin Shengming
College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases, Dalian, China.
Front Cell Dev Biol. 2023 Apr 12;11:919297. doi: 10.3389/fcell.2023.919297. eCollection 2023.
Chronic stress exposure is the main environmental factor leading to cognitive impairment, but the detailed molecular mechanism is still unclear. Adenosine Deaminase acting on double-stranded RNA1(ADAR1) is involved in the occurrence of chronic stress-induced cognitive impairment. In addition, dopamine and Adenosine 3'5'-monophosphate-regulated phospho-protein (DARPP-32) gene variation affects cognitive function. Therefore, we hypothesized that ADAR1 plays a key role in chronic stress-induced cognitive impairment by acting on DARPP-32. In this study, postnatal 21-day-old male BALB/c mice were exposed to chronic unpredictable stressors. After that, the mice were treated with ADAR1 inducer/inhibitor. The cognitive ability and cerebral DARPP-32 protein expression of BALB/c mice were evaluated. In order to explore the link between ADAR1 and DARPP-32, the effects of ADAR1 high/low expression on DARPP-32 protein expression in vitro were detected. ADAR1 inducer alleviates cognitive impairment and recovers decreased DARPP-32 protein expression of the hippocampus and prefrontal cortex in BALB/c mice with chronic unpredictable stress exposure. In vivo and in vitro studies confirm the results predicted by bio-informatics; that is, ADAR1 affects DARPP-32 expression via miR-874-3p. The results in this study demonstrate that ADAR1 affects the expression of DARPP-32 via miR-874-3p, which is involved in the molecular mechanism of pathogenesis in chronic unpredictable stress-induced cognitive impairment. The new findings of this study provide a new therapeutic strategy for the prevention and treatment of stress cognitive impairment from epigenetics.
长期暴露于应激环境是导致认知障碍的主要环境因素，但其具体分子机制仍不清楚。作用于双链RNA1的腺苷脱氨酶（ADAR1）参与了慢性应激诱导的认知障碍的发生。此外，多巴胺和3',5'-环磷酸腺苷调节的磷蛋白（DARPP-32）基因变异会影响认知功能。因此，我们推测ADAR1通过作用于DARPP-32在慢性应激诱导的认知障碍中起关键作用。在本研究中，将出生后21天的雄性BALB/c小鼠暴露于慢性不可预测应激源。之后，用ADAR1诱导剂/抑制剂对小鼠进行处理。评估BALB/c小鼠的认知能力和脑内DARPP-32蛋白表达。为了探究ADAR1与DARPP-32之间的联系，检测了ADAR1高/低表达对体外DARPP-32蛋白表达的影响。ADAR1诱导剂可减轻慢性不可预测应激暴露的BALB/c小鼠的认知障碍，并恢复海马和前额叶皮质中降低的DARPP-32蛋白表达。体内和体外研究证实了生物信息学预测的结果；即ADAR1通过miR-874-3p影响DARPP-32表达。本研究结果表明，ADAR1通过miR-874-3p影响DARPP-32的表达，这参与了慢性不可预测应激诱导的认知障碍发病机制的分子机制。本研究的新发现为从表观遗传学角度预防和治疗应激性认知障碍提供了新的治疗策略。
