Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
PLoS One. 2013 May 22;8(5):e64990. doi: 10.1371/journal.pone.0064990. Print 2013.
Alzheimer's disease (AD) is a devastating neurological disease characterized by pathological proteolytic cleavage of tau protein, which appears to initiate death of the neurons. The objective of this study was to investigate whether a proteolytic fragment of the tau protein could serve as blood-based biomarker of cognitive function in AD.
We developed a highly sensitive ELISA assay specifically detecting an A Disintegrin and Metalloproteinase 10 (ADAM10)-generated fragment of tau (Tau-A). We characterized the assay in detail with to respect specificity and reactivity in healthy human serum. We used samples from the Tg4510 tau transgenic mice, which over-express the tau mutant P301L and exhibit a tauopathy with similarities to that observed in AD. We used serum samples from 21 well-characterized Alzheimer's patients, and we correlated the Tau-A levels to cognitive function.
The Tau-A ELISA specifically detected the cleavage sequence at the N-terminus of a fragment of tau generated by ADAM10 with no cross-reactivity to intact tau or brain extracts. In brain extracts from Tg4510 mice compared to wt controls we found 10-fold higher levels of Tau-A (p<0.001), which indicates a pathological relevance of this marker. In serum from healthy individuals we found robust and reproducible levels of Tau-A, indicating that the analyte is present in serum. In serum from AD patients an inverse correlation (R² = 0.46, p<0.001) between the cognitive assessment score (Mattis Dementia Rating Scale (MDRS)) and Tau-A levels was observed.
Based on the hypothesis that tau is cleaved proteolytically and then released into the blood, we here provide evidence for the presence of an ADAM10-generated tau fragment (Tau-A) in serum. In addition, the levels of Tau-A showed an inverse correlation to cognitive function, which could indicate that this marker is a serum marker with pathological relevance for AD.
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其特征是tau 蛋白的病理性蛋白水解裂解，这似乎引发了神经元的死亡。本研究的目的是探讨 tau 蛋白的蛋白水解片段是否可以作为 AD 认知功能的基于血液的生物标志物。
我们开发了一种高度敏感的 ELISA 测定法，专门检测 tau 蛋白的 A 型分裂素金属蛋白酶 10（ADAM10）生成片段（Tau-A）。我们详细描述了该测定法在健康人血清中的特异性和反应性。我们使用了过度表达 tau 突变 P301L 的 Tg4510 tau 转基因小鼠的样本，并表现出与 AD 观察到的相似的 tau 病。我们使用了 21 个特征明确的 AD 患者的血清样本，并将 Tau-A 水平与认知功能相关联。
Tau-A ELISA 特异性检测到由 ADAM10 在 tau 的 N 端产生的片段的裂解序列，与完整 tau 或脑提取物无交叉反应。与 wt 对照相比，在 Tg4510 小鼠的脑提取物中，我们发现 Tau-A 的水平高出 10 倍（p<0.001），这表明该标志物具有病理性意义。在健康个体的血清中，我们发现了稳健且可重复的 Tau-A 水平，表明该分析物存在于血清中。在 AD 患者的血清中，认知评估评分（Mattis 痴呆评定量表（MDRS））与 Tau-A 水平之间存在负相关（R²=0.46，p<0.001）。
基于 tau 蛋白被蛋白水解裂解然后释放到血液中的假设，我们在此提供了 ADAM10 生成的 tau 片段（Tau-A）存在于血清中的证据。此外，Tau-A 的水平与认知功能呈负相关，这可能表明该标志物是一种具有 AD 病理性相关性的血清标志物。
