中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 3139-3148.doi: 10.4103/NRR.NRR-D-25-00851

• 原著:退行性病与再生 • 上一篇    下一篇

海马体昼夜节律转录组紊乱出现在阿尔茨海默病模型小鼠的认知缺陷之前#br#
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  • 出版日期:2026-07-15 发布日期:2026-04-01
  • 基金资助:
    深圳市科技和创新委员会（JCYJ20220531100811026）；深圳市创伤治疗临床研究中心（LCYSSQ20220823091405012）；深圳市科技专项（KQTD20240729102249044）

Circadian transcriptomic disruptions in the hippocampus precede cognitive deficits in an Alzheimer’s mouse model

Anlin Qi1, Yuxian He1, Feng Zhang1, Shiyan Liu1, Qiuan Xiang1, Yanqiong Dong2, Bin Wang3, Yingying Zhao1, *   

  1. 1Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, Guangdong Province, China; 
    2Department of Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China; 
    3He Sheng Zhi Li (Shenzhen) Health Technology Co.,Ltd., Shenzhen, Guangdong Province, China

  • Online:2026-07-15 Published:2026-04-01
  • Contact: Yingying Zhao, MD, zhaoyingying@szu.edu.cn.
  • Supported by:
    This work was supported by Shenzhen Science Technology and Innovation Commission, No. JCYJ20220531100811026; Shenzhen Clinical Research Center for Trauma Treatment, No. LCYSSQ20220823091405012 (both to YZ); Shenzhen Science and Technology Program, No. KQTD20240729102249044.

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摘要：

昼夜节律紊乱可能与阿尔茨海默病的发病和进展相关。然而，目前尚不清楚这种紊乱是否发生在认知症状出现之前，以及它是否驱动疾病发展。阐明昼夜节律紊乱与早期阿尔茨海默病病理变化的时间关联，或将为疾病预防与干预开辟新路径。为验证昼夜节律紊乱是否先于认知衰退发生，此课题组对5月龄阿尔茨海默病小鼠及同龄野生型对照组小鼠的海马区进行了24 h多时间点高分辨率转录组分析结果显示，尽管该阶段阿尔茨海默病小鼠尚未出现明显认知症状，其海马体中昼夜节律相关基因的表达已呈现广泛异常。在对照组中，共鉴定出2109个具有节律性表达特征的基因；在阿尔茨海默病模型小鼠中，这些基因中有相当一部分丧失节律性，部分基因出现新节律性，或维持节律性但表达模式发生改变。与神经元功能相关的基因（包括参与蛋白质稳态调节、神经炎症及离子稳态的基因）其昼夜节律振幅和相位均发生显著变化，部分基因甚至完全丧失节律性。这些发现揭示了阿尔茨海默病的关键早期事件：海马区昼夜节律基因紊乱发生于认知症状出现之前，神经功能相关基因对这种早期失调具有独特易感性，且此类昼夜节律功能障碍甚至可能先于阿尔茨海默病病理变化影响疾病发作。该研究明确了昼夜节律紊乱是症状出现前的早期事件，锁定可作为干预靶点的神经通路，并强化昼夜节律调控作为早期干预策略的潜力。


https://orcid.org/0000-0003-0642-0105 (Yingying Zhao)

关键词: 阿尔茨海默病, 认知衰退, 昼夜节律紊乱, 昼夜节律相关基因, 离子稳态, 神经通路失调, 神经炎症, 神经元功能, 蛋白质稳态, 转录组分析

Abstract: Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer’s disease. However, whether this disruption occurs before the appearance of cognitive symptoms and whether it drives disease development remain unclear. Understanding the temporal relationship between circadian rhythm dysregulation and early Alzheimer’s disease pathological changes may open up new avenues for disease prevention and intervention. To determine if circadian rhythm disruption precedes cognitive decline, we conducted high-resolution transcriptome analyses of the hippocampus in a 5-month-old mouse model of Alzheimer’s disease and age-matched wild-type control mice at multiple time points over a 24-hour period. While the mouse model of Alzheimer’s disease did not exhibit obvious cognitive symptoms at this stage, the expression of circadian-related genes in the hippocampus exhibited extensive abnormalities. In the control group, 2109 genes exhibited rhythmic expression characteristics. In the mouse model of Alzheimer’s disease, a marked proportion of these genes lost their rhythmicity, some genes newly developed rhythmicity, and some maintained rhythmicity but with altered expression patterns. Genes related to neuronal function, including those involved in protein homeostasis regulation, neuroinflammation, and ion homeostasis, showed significant changes in circadian rhythm amplitude and phase, and some completely lost their rhythmicity. These findings point to the following critical early events in Alzheimer’s disease: hippocampal circadian gene disruption occurs before cognitive symptoms emerge, genes related to neuronal function are uniquely susceptible to this early dysregulation, and circadian dysfunction may even precede the pathological changes of Alzheimer’s disease and influence disease onset. This work advances Alzheimer’s disease research by clarifying that circadian disruption is an early pre-symptomatic event, reinforcing the potential of circadian rhythm regulation as a strategy for early intervention of Alzheimer’s disease, and identifying neuronal pathways that may serve as intervention targets. 

Key words: Alzheimer’s disease, circadian rhythm circadian-related genes, cognitive decline, ion homeostasis, neural pathway, neuroinflammation, neuronal function, protein homeostasis, transcriptome analysis