Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 212241, USA.
NeuroDex Inc., Natick, MA 01760, USA.
Cells. 2021 Apr 23;10(5):993. doi: 10.3390/cells10050993.
Circulating neuronal extracellular vesicles (NEVs) of Alzheimer's disease (AD) patients show high Tau and β-amyloid (Aβ) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. To validate EV proteins as AD biomarkers, we immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels. NEVs from 3xTg-AD mice had higher total Tau ( = 0.03) and p181-Tau ( = 0.0004) compared to WT mice. There were moderately strong correlations between biomarkers in NEVs and cerebral cortex and hippocampus (total Tau: cortex, r = 0.4, = 0.009; p181-Tau: cortex, r = 0.7, < 0.0001; hippocampus, r = 0.6, < 0.0001). NEVs from 5xFAD compared to other mice had higher Aβ42 ( < 0.005). NEV Aβ42 had moderately strong correlations with Aβ42 in cortex (r = 0.6, = 0.001) and hippocampus (r = 0.7, < 0.0001). AEV C1q was elevated in 3xTg-AD compared to WT mice ( = 0.005); AEV C1q had moderate-strong correlations with C1q in cortex (r = 0.9, < 0.0001) and hippocampus (r = 0.7, < 0.0001). Biomarkers in circulating NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as a "liquid biopsy" for neurological disorders.
阿尔茨海默病（AD）患者的循环神经元细胞外囊泡（NEV）显示出高 Tau 和 β-淀粉样蛋白（Aβ）水平，而其星形胶质细胞 EV（AEV）含有高水平的补体。为了验证 EV 蛋白作为 AD 生物标志物的作用，我们从 15 只野生型（WT）、4 只 2xTg-AD、9 只 5xFAD 和 15 只 3xTg-AD 小鼠的血浆中免疫捕获了 NEV 和 AEV，并评估了生物标志物与脑组织水平的关系。与 WT 小鼠相比，3xTg-AD 小鼠的 NEV 中总 Tau（ = 0.03）和 p181-Tau（ = 0.0004）水平更高。NEV 中的生物标志物与大脑皮层和海马体之间存在中度强相关性（总 Tau：皮层，r = 0.4， = 0.009；p181-Tau：皮层，r = 0.7， < 0.0001；海马体，r = 0.6， < 0.0001）。与其他小鼠相比，5xFAD 小鼠的 NEV 中 Aβ42 水平更高（ < 0.005）。NEV Aβ42 与皮层（r = 0.6， = 0.001）和海马体（r = 0.7， < 0.0001）中的 Aβ42 之间存在中度强相关性。与 WT 小鼠相比，3xTg-AD 小鼠的 AEV C1q 升高（ = 0.005）；AEV C1q 与皮层（r = 0.9， < 0.0001）和海马体（r = 0.7， < 0.0001）中的 C1q 之间存在中度强相关性。循环 NEV 和 AEV 中的生物标志物反映了它们在多种 AD 小鼠模型中的大脑水平，支持它们作为神经疾病“液体活检”的潜在用途。
