Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.

IF 4.8 2区医学 Q1 CLINICAL NEUROLOGY Journal of Neurology Pub Date : 2025-01-15 DOI:10.1007/s00415-024-12824-0

Chunsong Zhao, Taoran Li, Shuwen Hao, Lifang Zhao, Ying Han, Yanning Cai

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Abstract

Background: Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms.

Methods: Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging.

Results: The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups.

Conclusions: This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis.

Trial registration: The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15^th, 2017).

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阿尔茨海默病患者血源性因素对分子钟的失调。

背景：在阿尔茨海默病（AD）患者中越来越多地认识到昼夜节律中断，并可能影响疾病的发生和进展。本研究探讨了AD病理如何影响调节昼夜节律的血源性因子。方法：85名来自中国认知衰退纵向研究的参与者：35名β-淀粉样蛋白阴性正常对照（Aβ- nc）， 23名β-淀粉样蛋白阳性正常对照（Aβ+ nc）， 15名遗忘性轻度认知障碍（aMCI）患者，12名阿尔茨海默病痴呆（ADD）患者。合并aMCI和ADD的患者分为认知障碍组（CI）。使用基于血清的测定法评估细胞昼夜周期长度。通过实时聚合酶链反应（real-time PCR）检测血清处理细胞和白细胞中时钟基因的表达水平。血浆生物标志物定量使用单分子阵列免疫分析法。磁共振成像测定松果体实质和海马体积。结果：CI患者血清的细胞昼夜周期长度明显延长（p < 0.01）。用CI患者的血清处理细胞可抑制时钟基因Bmal1和Nr1d1的表达。在Aβ- NC组白细胞中观察到的时钟基因表达水平之间的强相关性在Aβ+ NC组和CI组中没有出现。细胞昼夜周期长度与松果体体积的相关性仅在Aβ- NC组存在，而在Aβ+ NC和CI组均无显著相关性。结论：本研究表明，血源性因素的显著变化可能影响AD患者的昼夜节律，甚至在临床前阶段就开始了。这些改变可能先于认知能力下降，并有助于AD的发病。试验注册：该队列在ClinicalTrials.gov上注册(SILCODE: NCT03370744；2017年3月15日注册)。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neurology 医学-临床神经学

CiteScore

10.00

自引率

5.00%

发文量

558

审稿时长

1 months

期刊介绍： The Journal of Neurology is an international peer-reviewed journal which provides a source for publishing original communications and reviews on clinical neurology covering the whole field. In addition, Letters to the Editors serve as a forum for clinical cases and the exchange of ideas which highlight important new findings. A section on Neurological progress serves to summarise the major findings in certain fields of neurology. Commentaries on new developments in clinical neuroscience, which may be commissioned or submitted, are published as editorials. Every neurologist interested in the current diagnosis and treatment of neurological disorders needs access to the information contained in this valuable journal.