Isolation and characterization of antibody fragment selective for human Alzheimer's disease brain-derived tau variants.
Isolation and characterization of antibody fragment selective for human Alzheimer's disease brain-derived tau variants.
复制标题
对人类阿尔茨海默病脑源性 tau 变体具有选择性的抗体片段的分离和表征。
DOI：
10.1016/j.neurobiolaging.2020.04.014
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发表时间：
2020
影响因子：
4.2
通讯作者：
Sierks,MichaelR
中科院分区：
文献类型：
--
作者：
Venkataraman,Lalitha;He,Ping;Schulz,Philip;Sierks,MichaelR
可以选择性识别与阿尔茨海默病（AD）和其他tau蛋白病的发作和进展相关的特定毒性tau变体的试剂可以是有效的诊断和治疗工具。我们利用一种新的基于原子力显微镜的生物淘选方案来分离抗体片段（单链可变片段，scFv），所述抗体片段选择性地结合存在于人AD中的tau变体，但不结合认知正常的年龄匹配的脑组织。我们鉴定了容易区分AD和对照组织和血清样品的6种scFv [阿尔茨海默病tau（ADT）-1至6]。我们利用3种scFv（ADT-2、ADT-4和ADT-6）分析来自50名人类患者的纵向血浆样品，其中25名患者在研究期间转化为AD，25名患者保持认知正常。所有3种scFv都可以区分AD与对照样品，与载脂蛋白E3/4相比，载脂蛋白E3/3 AD病例中的tau水平更高。人类AD脑切片的免疫组织化学分析表明，有几个但不是所有的tau变体与磷酸化tau染色重叠。几种试剂也显示出治疗潜力，保护神经元细胞免受AD tau诱导的毒性。
Reagents that can selectively recognize specific toxic tau variants associated with onset and progression of Alzheimer’s disease (AD) and other tauopathies can be effective diagnostic and therapeutic tools. We utilized a novel atomic force microscopy–based biopanning protocol to isolate antibody fragments (single chain variable fragments, scFvs) that selectively bind tau variants present in human AD but not cognitively normal age-matched brain tissue. We identified 6 scFvs [Alzheimer's disease tau (ADT)-1 through 6] that readily distinguished between AD and control tissue and sera samples. We utilized 3 of the scFvs (ADT-2, ADT-4, and ADT-6) to analyze longitudinal plasma samples from 50 human patients, 25 patients which converted to AD during the study and 25 that remained cognitively normal. All 3 scFvs could distinguish the AD from control samples with higher tau levels in apolipoprotein E3/3 AD cases compared to apolipoprotein E3/4. Immunohistochemical analyses of human AD brain slices indicated several but not all tau variants overlapping with phosphorylated tau staining. Several reagents also showed therapeutic potential, protecting neuronal cells against AD tau-induced toxicity.