Abstract

Background:

Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

Objective:

We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

Methods:

We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

Results:

We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

Conclusions:

Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

中文翻译：

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Dickkopf-1 体外过表达指定了与阿尔茨海默病病理学相关的候选血液生物标志物。

摘要

背景：

以前的研究表明，Dickkopf-1 (DKK1) 是 Wnt 信号传导的抑制剂，在淀粉样蛋白诱导的毒性和阿尔茨海默病 (AD) 中起作用。然而，DKK1 表达对蛋白质表达的影响以及这些蛋白质在疾病中是否发生改变尚不清楚。

客观的：

我们旨在测试体外获得的 DKK1 诱导的蛋白质特征是否与淀粉样蛋白/tau/神经变性 (ATN) 框架中使用的 AD 病理标志物以及临床结果相关。

方法：

我们首先在 HEK293A 细胞中过表达 DKK1，并使用适体捕获阵列 (SomaScan) 量化细胞裂解物中的 1,128 种蛋白质，以获得由 DKK1 诱导的蛋白质特征。然后，我们使用相同的测定法在两个大队列中测量人血浆中的 DKK1 特征蛋白，EMIF（n = 785）和 ANM（n = 677）。

结果：

我们在体外鉴定了 DKK1 诱导的 100 种蛋白质特征。蛋白质亚组以及年龄和载脂蛋白 E ɛ 4 基因型区分了淀粉样蛋白病理（A + T–N–、A+T+N–、A+T–N+ 和 A+T+N+）与无 AD 病理（A –T–N–) 曲线下面积分别为 0.72、0.81、0.88 和 0.85。此外，我们发现一些特征蛋白（例如补体 C3 和白蛋白）与两个队列中的认知评分和 AD 诊断相关。

结论：

我们的结果进一步证明了 DKK 对 Wnt 信号传导在 AD 中的调节作用，并表明体外获得的 DKK1 诱导的特征蛋白可以反映 ATN 框架并预测体内疾病的严重程度和进展。