Isolation and characterization of antibody fragment selective for human Alzheimer’s disease brain-derived tau variants

• Published in: Neurobiology of aging Vol. 94; pp. 7 - 14
• Main Authors: Venkataraman, Lalitha, He, Ping, Schulz, Philip, Sierks, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2020
• Subjects: Alzheimer’s disease; Biomarker; Single chain antibody fragment; Tau; Tau; Biomarker; Alzheimer’s disease; Single chain antibody fragment
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.04.014

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. •Identified antibody fragments that selectively bind tau variants present in human postmortem AD brain tissue.•All reagents selectively react with human postmortem AD brain tissue and sera samples but not age-matched cognitively normal control samples.•Reagents selectively react with longitudinal human plasma samples from patients that converted to AD indicating early, presymptomatic diagnostic capability.•Reagents selectively label tau variants in human brain tissue samples.•Reagents block toxicity of tua variants isolated from human AD brain tissue toward a human neuronal cell line.