Williams Stephanie M, Schulz Philip, Rosenberry Terrone L, Caselli Richard J, Sierks Michael R
Chemical Engineering, The School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, USA.
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
J Alzheimers Dis. 2017;58(1):23-35. doi: 10.3233/JAD-161116.
Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer's disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis. While the subsequent diagnoses for the cases covered several different conditions, all samples had elevated protein variant levels relative to the plasma controls although with different individual biomarker profiles. We then analyzed a set of longitudinal human plasma samples from four AD (encompassing time points prior to MCI diagnosis and continuing until after conversion to AD) and two control cases. Pre-MCI samples were characterized by high TDP-43 variant levels, MCI samples by high Aβ variant levels, and AD samples by high Aβ and tau variant levels. Sample time points ranged from ∼7 years pre-MCI to ∼9 years after AD conversion. Bivariate correlations showed a negative correlation with TDP-43 levels and positive correlations with cumulative Aβ and oligomeric tau levels indicating an increase in neurodegenerative processes with time in AD. Detection of disease related protein variants not only readily selects AD cases from controls, but also stages progression of AD and holds promise for a pre-symptomatic blood-based biomarker profile for AD.
淀粉样β蛋白（Aβ）、tau蛋白和TDP - 43的寡聚体形式在阿尔茨海默病（AD）中起重要作用，因此是很有前景的生物标志物。我们之前制备了单链抗体片段（scFvs），它们能选择性结合这些蛋白质的疾病相关变体，包括A4、C6T和E1，它们结合不同的寡聚体Aβ变体；D11C，它结合寡聚体tau蛋白；以及AD - TDP1和AD - TDP2，它们结合疾病相关的TDP - 43变体。为了确定这些疾病相关变体作为早期生物标志物的效用，我们首先分析了11份在首次轻度认知障碍（MCI）诊断前约2年采集的人类血清样本。虽然这些病例随后的诊断涵盖了几种不同情况，但所有样本相对于血浆对照的蛋白质变体水平都有所升高，尽管个体生物标志物谱不同。然后我们分析了一组来自4例AD患者（涵盖MCI诊断前的时间点并持续到转化为AD之后）和2例对照病例的纵向人类血浆样本。MCI前样本的特征是TDP - 43变体水平高，MCI样本的特征是Aβ变体水平高，而AD样本的特征是Aβ和tau变体水平高。样本时间点从MCI前约7年到AD转化后约9年。双变量相关性分析显示，与TDP - 43水平呈负相关，与累积Aβ和寡聚体tau水平呈正相关，表明AD中神经退行性过程随时间增加。检测疾病相关蛋白质变体不仅能轻松地从对照中筛选出AD病例，还能对AD的进展进行分期，并有望为AD建立基于血液的症状前生物标志物谱。
