Hadjidemetriou Marilena, Rivers-Auty Jack, Papafilippou Lana, Eales James, Kellett Katherine A B, Hooper Nigel M, Lawrence Catherine B, Kostarelos Kostas
Nanomedicine Lab, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, United Kingdom.
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
ACS Nano. 2021 Apr 27;15(4):7357-7369. doi: 10.1021/acsnano.1c00658. Epub 2021 Mar 17.
Blood-circulating biomarkers have the potential to detect Alzheimer's disease (AD) pathology before clinical symptoms emerge and to improve the outcomes of clinical trials for disease-modifying therapies. Despite recent advances in understanding concomitant systemic abnormalities, there are currently no validated or clinically used blood-based biomarkers for AD. The extremely low concentration of neurodegeneration-associated proteins in blood necessitates the development of analytical platforms to address the "signal-to-noise" issue and to allow an in-depth analysis of the plasma proteome. Here, we aimed to discover and longitudinally track alterations of the blood proteome in a transgenic mouse model of AD, using a nanoparticle-based proteomics enrichment approach. We employed blood-circulating, lipid-based nanoparticles to extract, analyze and monitor AD-specific protein signatures and to systemically uncover molecular pathways associated with AD progression. Our data revealed the existence of multiple proteomic signals in blood, indicative of the asymptomatic stages of AD. Comprehensive analysis of the nanoparticle-recovered blood proteome by label-free liquid chromatography-tandem mass spectrometry resulted in the discovery of AD-monitoring signatures that could discriminate the asymptomatic phase from amyloidopathy and cognitive deterioration. While the majority of differentially abundant plasma proteins were found to be upregulated at the initial asymptomatic stages, the abundance of these molecules was significantly reduced as a result of amyloidosis, suggesting a disease-stage-dependent fluctuation of the AD-specific blood proteome. The potential use of the proposed nano-omics approach to uncover information in the blood that is directly associated with brain neurodegeneration was further exemplified by the recovery of focal adhesion cascade proteins. We herein propose the integration of nanotechnology with already existing proteomic analytical tools in order to enrich the identification of blood-circulating signals of neurodegeneration, reinvigorating the potential clinical utility of the blood proteome at predicting the onset and kinetics of the AD progression trajectory.
血液循环生物标志物有潜力在临床症状出现之前检测出阿尔茨海默病（AD）的病理变化，并改善疾病修饰疗法的临床试验结果。尽管在理解伴随的全身异常方面取得了最新进展，但目前尚无经过验证或临床应用的用于AD的血液生物标志物。血液中与神经退行性变相关蛋白质的浓度极低，因此需要开发分析平台来解决“信噪比”问题，并对血浆蛋白质组进行深入分析。在此，我们旨在使用基于纳米颗粒的蛋白质组学富集方法，在AD转基因小鼠模型中发现并纵向追踪血液蛋白质组的变化。我们利用血液循环的、基于脂质的纳米颗粒来提取、分析和监测AD特异性蛋白质特征，并系统地揭示与AD进展相关的分子途径。我们的数据揭示了血液中存在多种蛋白质组信号，表明AD处于无症状阶段。通过无标记液相色谱 - 串联质谱对纳米颗粒回收的血液蛋白质组进行综合分析，发现了能够区分无症状期与淀粉样变性和认知衰退的AD监测特征。虽然大多数差异丰富的血浆蛋白在最初的无症状阶段被发现上调，但由于淀粉样变性，这些分子的丰度显著降低，这表明AD特异性血液蛋白质组存在疾病阶段依赖性波动。粘着斑级联蛋白的回收进一步例证了所提出的纳米组学方法在揭示与脑神经元变性直接相关的血液信息方面的潜在用途。我们在此提议将纳米技术与现有的蛋白质组分析工具相结合，以丰富对神经退行性变血液循环信号的识别，重振血液蛋白质组在预测AD进展轨迹的发病和动力学方面的潜在临床应用价值。
