Department of Pharmacology, College of Medicine, Gachon University, Incheon 21936, Korea.
Neuroscience Research Institute, Gachon University, Incheon 21565, Korea.
Int J Mol Sci. 2020 Jul 15;21(14):5007. doi: 10.3390/ijms21145007.
Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer's disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age-matched controls (AMC, = 26), mild cognitive impairment group (MCI, = 30), and mild-AD group ( = 20) according to the Mini-mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t-tau, but not p-tau, was significantly higher in the mild-AD group than AMC subjects ( < 0.05), and there were significant correlations of serum t-tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild-AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell-derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood-brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t-tau and p-tau (S202) were significantly higher in the mild-AD group compared to AMC ( < 0.05) and MCI groups ( < 0.01). In contrast, serum amyloid β (Aβ) was lower in the mild-AD group compared to MCI groups ( < 0.001). During the 4-year follow-up, NEX t-tau and p-tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t-tau and p-tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression.
脑脊液（CSF）中总 tau（t-tau）和磷酸化 tau（p-tau）蛋白的升高是阿尔茨海默病（AD）的公认标志，而血清 t-tau 和 p-tau 水平与 AD 的相关性在不同研究中并不一致。为了确定更易获得的非侵入性 AD 生物标志物，我们根据 Mini-mental State Examination（MMSE）、Clinical Dementia Rating（CDR）和 Global Deterioration Scale（GDS）评分，测量了年龄匹配的对照组（AMC，n=26）、轻度认知障碍组（MCI，n=30）和轻度 AD 组（n=20）中的血清 tau 蛋白，并分析了其与认知功能的相关性。与 AMC 受试者相比，轻度 AD 组的血清 t-tau 而非 p-tau 显著升高（p<0.05），且血清 t-tau 与 MMSE 和 GDS 评分呈显著相关。受试者工作特征（ROC）分析显示，轻度 AD 与 AMC 受试者的区分具有中等敏感性和特异性（AUC=0.675）。我们推测，从血清中分离的神经元细胞衍生外泌体（NEX）中的 tau 蛋白与脑 tau 水平和疾病特征的相关性更强，因为这些外泌体可以穿透血脑屏障。事实上，ELISA 和 Western blot 分析表明，与 AMC（p<0.05）和 MCI（p<0.01）组相比，轻度 AD 组的 NEX t-tau 和 p-tau（S202）均显著升高。相比之下，与 MCI 组相比，轻度 AD 组的血清淀粉样蛋白β（Aβ）水平更低（p<0.001）。在 4 年的随访期间，NEX t-tau 和 p-tau（S202）水平与 GDS 和 MMSE 评分的变化相关。在表达人类 tau 突变的 JNPL3 转基因（Tg）小鼠中，随着神经病理学进展，NEX 中的 t-tau 和 p-tau 表达水平增加，并且 NEX tau 与脑组织外泌体（tEX）中的 tau 相关，表明 tau 蛋白通过外泌体进入循环。总之，我们的数据表明，血清 tau 蛋白，尤其是 NEX tau 蛋白，是监测 AD 进展的有用生物标志物。
