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.

中文翻译：

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对人 AD 脑源性 tau 变体具有选择性的抗体片段的分离和表征

可以选择性识别与阿尔茨海默病 (AD) 和其他 tauo 病的发生和进展相关的特定毒性 tau 变异体的试剂可以成为有效的诊断和治疗工具。我们利用一种基于原子力显微镜的新型生物淘选方案来分离抗体片段（单链可变片段，scFvs），这些片段选择性地结合人类 AD 中存在的 tau 变异，但不结合认知正常的年龄匹配脑组织。我们鉴定了 6 个 scFvs [阿尔茨海默病 tau (ADT)-1 到 6]，它们很容易区分 AD 和对照组织和血清样本。我们利用 3 个 scFv（ADT-2、ADT-4 和 ADT-6）分析了来自 50 名人类患者的纵向血浆样本，其中 25 名患者在研究期间转变为 AD，25 名保持认知正常。与载脂蛋白 E3/4 相比，在载脂蛋白 E3/3 AD 病例中，所有 3 个 scFv 都可以将 AD 与具有更高 tau 水平的对照样品区分开来。人 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 变体与磷酸化的 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。