Hollis Henry C, Sharma Ashish, Sheehan Patrick W, Maggi Leonard B, Weber Jason D, Hammarlund Jan A, Bennett David A, Menon Vilas, Musiek Erik S, Anafi Ron C
School of Biomedical Engineering and Health Systems, Drexel University, Philadelphia, PA, USA.
Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
Neuron. 2025 Aug 6. doi: 10.1016/j.neuron.2025.07.010.
Alzheimer's disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing (snRNA-seq) from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia, reconstructing circadian expression profiles across cell types. Although core clock rhythms were preserved in AD, many cell-type-specific circadian outputs were disrupted. Rhythms in ribosomal biogenesis and oxidative phosphorylation were dampened across cell types. Similar losses in ribosomal gene expression rhythms were observed in amyloid precursor protein/presenilin 1 (APP/PS1) mice, which showed further reductions in ribosomal protein expression and polysome-mediated translation after circadian desynchrony. Exploratory computational modeling reveals that altered translation may contribute to the increased circadian variability seen in AD patients. These findings reveal altered cell-type-specific circadian output rhythms in the brains of AD-affected patients and highlight disrupted ribosomal rhythms as a feature of AD.
阿尔茨海默病（AD）会扰乱行为昼夜节律，但其对人类大脑分子节律的影响却知之甚少。通过对死后皮质样本进行单核RNA测序（snRNA-seq），我们从信息学角度估计了409名患有和未患AD痴呆症患者的相对昼夜节律相位，重建了不同细胞类型的昼夜表达谱。尽管AD患者大脑中的核心生物钟节律得以保留，但许多细胞类型特异性的昼夜输出受到了干扰。核糖体生物合成和氧化磷酸化的节律在所有细胞类型中均受到抑制。在淀粉样前体蛋白/早老素1（APP/PS1）小鼠中也观察到核糖体基因表达节律出现类似的损失，这些小鼠在昼夜节律失调后，核糖体蛋白表达和多核糖体介导的翻译进一步减少。探索性计算模型表明，翻译改变可能导致AD患者中观察到的昼夜节律变异性增加。这些发现揭示了AD患者大脑中细胞类型特异性昼夜输出节律的改变，并突出了核糖体节律紊乱是AD的一个特征。
