Wnt/β-catenin信号通路在介导慢性间歇低氧所致的海马突触可塑性异常和认知功能障碍中的机制作用

Obstructive sleep apnea-hypoxia syndrome (OSAHS) has a high co-morbidity with Alzheimer's Disease (AD) and can negatively impact functioning in multiple cognitive domains, such as memory, attention, vigilance and executive functioning. The underlying mechanisms are unclear. Cumulative evidence suggests that chronic intermittent hypoxia (CIH) and fragmented sleep, which are direct consequences of OSAHS, can lead to structural changes in the brain, neuronal cell loss as well as synaptic plasticity deficits and subsequently result in neurocognitive dysfunction. Wnt signaling pathway participates in the regulation of adult hippocampal neurogenesis, maintenance of nervous system functioning in adult animals and the process of neurodegenerative diseases. Thus we try to investigate the regulatory mechanisms for Wnt/β-catenin signaling pathway in mediating hippocampal neuron apoptosis, synaptic pasticity impairment and subsequently neurocognitive deficits induced by chronic intermittent hypoxia with the use of RNA interference (RNAi) methods or pharmacological inhibitors to block Wnt/β-catenin signaling pathway. We hope the researches will provide new insight into the molecular mechanisms underlying CIH-associated cognitive impairment and manipulation of the Wnt/β-catenin pathway could be potential targets for the future treatment in OSA-induced neurocognitive dysfunction.

阻塞性呼吸暂停低通气综合征（OSAHS）导致的认知功能障碍集中表现在记忆力、注意力、警觉性、执行能力等方面的功能受损，其与阿尔茨海默病存在较高共病率。OSAHS继发认知损害机制不清,慢性间歇低氧（CIH）和睡眠结构紊乱造成神经系统尤其是海马结构破坏是引起以记忆损害为主的认知功能障碍的病理生理基础，神经元凋亡和突触可塑性异常贯穿于认知障碍的全过程。Wnt信号通路参与成体神经元再生、神经系统功能维持和神经退行性疾病的发生演变。本课题旨在探讨Wnt/β-catenin通路在介导CIH所致的海马神经元丢失和突触可塑性异常引发认知功能障碍中的作用，并利用Wnt/β-catenin通路关键信号分子的化学阻滞剂或基因手段（RNA干扰技术,RNAi）特异性地阻断该通路的信号转导环节了解神经元凋亡、突触可塑性损伤和认知功能的改善情况，以期为CIH所并发的认知功能损害提供更深入的分子机制的阐释和治疗思路。

阻塞性呼吸暂停（OSA）导致的认知功能障碍集中表现在记忆力、注意力、警觉性、执行能力等方面的功能受损。人外周血单核细胞蛋白水平的检测提示OSA患者组β –catenin表达减少；与对照组相比，患者组总GSK-3β无变化，但p- GSK-3β在患者组较多；DvL、CK1ε在患者组较少。慢性间歇缺氧（CIH）暴露使小鼠海马β–catenin水平减少，认知功能受损。Wnt/β-catenin通路激活剂Licl可改善CIH引起的小鼠海马神经元凋亡和认知功能障碍。鼠海马区注射RNAi病毒载体特异性地阻断GSK-3β的表达水平亦可改善CIH小鼠海马神经元超微结构损伤、神经元凋亡和认知功能障碍。我们认为在CIH所致的海马神经元损伤、认知功能障碍中，Wnt/β-catenin通路起到重要作用。