Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, F-75013, Paris, France.
Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, F-75013, Paris, France.
Transl Psychiatry. 2021 Jan 27;11(1):78. doi: 10.1038/s41398-020-01184-8.
There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and F-fluorodeoxyglucose-PET (F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15btime interaction on regional metabolic F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125btime interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.
有大量实验证据表明，阿尔茨海默病（AD）患者的几种 microRNA（miRNA）表达水平失调。miRNA 调节关键的脑内信号通路，并与 AD 的核心病理生理机制相关。首先，我们进行了一项基于实时定量 PCR 的初步研究，以确定一组在有主观记忆主诉的认知正常个体的单中心队列中富含大脑的 miRNA，这种情况与 AD 风险增加有关。其次，我们研究了年龄、性别和载脂蛋白 E ε4（APOE ε4）等位基因对鉴定出的 miRNA 血浆浓度的影响。此外，我们还探索了 miRNA 血浆浓度与使用淀粉样蛋白-β（Aβ）正电子发射断层扫描（Aβ-PET）和 F-氟脱氧葡萄糖-PET（F-FDG-PET）的区域性脑代谢摄取之间的横断面和纵向关联。我们确定了一组六个富含大脑的 miRNA-miRNA-125b、miRNA-146a、miRNA-15b、miRNA-148a、miRNA-26b 和 miRNA-100。年龄、性别和 APOE ε4 等位基因与单个 miRNA 丰度无关。与 Aβ-PET 阴性个体相比，Aβ-PET 阳性个体的 miRNA-15b 浓度明显降低。此外，我们发现 miRNA-15b时间相互作用对左侧海马体的区域性代谢 F-FDG-PET 摄取有正向影响。在 2 年的随访中，miRNA-125b 浓度以及 miRNA-125b时间相互作用（在 2 年的随访中）与右侧前扣带回皮质的区域 Aβ-PET 标准摄取值比呈负相关。在基线时，我们发现血浆 miRNA-125b 浓度与特定脑区的 F-FDG-PET 摄取之间存在显著负相关。在 AD 无症状高危人群中，我们发现 miRNA-125b 和 miRNA-15b 的血浆浓度与 AD 病理生理学的核心神经影像学生物标志物之间存在显著关联。我们的结果结合现有的实验证据表明，miRNA-15b 可能具有抗 Aβ 的保护作用，miRNA-125b 与 Aβ 无关的神经毒性途径之间存在生物学联系。
