龚奕 肖星洋 胡有生 谢义炜 伍知辉

摘要：阿尔茨海默病（AD）是一种严重威胁人类健康的疾病，也是引起人类死亡的三大因素之一。双链RNA依赖的蛋白激酶（PKR）又称为前炎症细胞因子，是人类先天免疫干扰素刺激因子之一。在AD发生和发展中，PKR表达上调并持续激活，一方面引发脑组织细胞发生整合应激反应，另一方面间接上调β位淀粉样前体蛋白裂解酶1的表达，促进β淀粉样蛋白（Aβ）的积累，而Aβ的积累又可以激活PKR，进一步促进Aβ的积累，形成一个Aβ持续积累的循环。PKR还可以促进Tau蛋白磷酸化，降低神经细胞微管稳定性。脑组织炎症反应、Aβ的积累所引起神经毒性和微管稳定性的破坏会导致AD发生发展，引起患者记忆和认知的下降，因此PKR是AD发生发展中的关键分子。有效进行PKR检测可以预测AD进展，为临床治疗AD提供先机。目前PKR已成为研发治疗AD药物的靶点，因此靶向PKR的抑制剂有望控制PKR的活性，从而有效控制AD发生发展。

关键词：阿尔茨海默病；双链RNA依赖的蛋白激酶；β淀粉样蛋白；Tau蛋白

中图分类号： R34  文献标识码： A  文章编号：1000-503X（2024）03-0425-10

DOI：10.3881/j.issn.1000-503X.15792

Research Advances in the Association Between Alzheimers Disease and Double-Stranded RNA-Dependent Protein Kinase

GONG Yi XIAO Xingyang HU Yousheng 2，XIE Yiwei3，WU Zhihui3

1Fuzhou Medical College，Nanchang University，Fuzhou，Jiangxi 344000，China

2Key Laboratory of Chronic Diseases of Fuzhou Medical College，Nanchang University，Fuzhou，Jiangxi 344000，China

3Health Science Center，Jinggangshan University，Jian，Jiangxi 343009，China

Corresponding author：HU Yousheng Tel：0794-825168 E-mail：huyousheng68@163.com

ABSTRACT：Alzheimers disease （AD） is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase （PKR） is an interferon-induced protein kinase involved in innate immunity.In the occurrence and development of AD，PKR is upregulated and continuously activated.On the one hand，the activation of PKR triggers an integrated stress response in brain cells.On the other hand，it indirectly upregulates the expression of β-site amyloid precursor protein cleaving enzyme 1 and facilitates the accumulation of amyloid-β protein （Aβ），which could activate PKR activator to further activate PKR，thus forming a sustained accumulation cycle of Aβ.In addition，PKR can promote Tau phosphorylation，thereby reducing microtubule stability in nerve cells.Inflammation in brain tissue，neurotoxicity resulted from Aβ accumulation，and disruption of microtubule stability led to the progression of AD and the declines of memory and cognitive function.Therefore，PKR is a key molecule in the development and progression of AD.Effective PKR detection can aid in the diagnosis and prediction of AD progression and provide opportunities for clinical treatment.The inhibitors targeting PKR are expected to control the activity of PKR，thereby controlling the progression of AD.Therefore，PKR could be a target for the development of therapeutic drugs for AD.

Key words：Alzheimers disease；double-stranded RNA-dependent protein kinase；amyloid-beta；Tau

Acta Acad Med Sin，2024，46（3）：425-434

阿尔茨海默病（Alzheimers disease，AD）是一种慢性神经退行性病变引起的疾病。轻度AD患者首先表现为轻度认知障碍，约15%的轻度患者在两年后病情会发展成中重度痴呆［1］。中度AD患者在记忆和语言方面会产生障碍，且难以完成洗澡和穿衣等日常事务。重度AD患者大脑中参与运动调节和控制吞咽的区域会受损，出现卧床不起、进食和饮水困难等症状［2］。有研究认为AD是一种复杂的疾病，由遗传和环境因素及其他复杂的原因（如性别、年龄和不良生活习惯等）导致［3］。……