Isolation and characterization of antibody fragments selective for toxic oligomeric tau

Neurobiol Aging. 2015 Mar;36(3):1342-55. doi: 10.1016/j.neurobiolaging.2014.12.002. Epub 2014 Dec 11.

Abstract

Oligomeric tau species are important in the onset and progression of Alzheimer's disease (AD), as they are neurotoxic and can propagate tau-tangle pathology. Therefore, reagents that selectively recognize different key morphologies of tau are needed to help define the role of tau in AD and related diseases. We utilized a biopanning protocol that combines the binding diversity of phage-displayed antibody libraries with the powerful imaging capability of atomic force microscopy to isolate single-chain antibody fragments (scFvs) that selectively bind toxic oligomeric tau. We isolated 3 different antibody fragments that bind oligomeric but not monomeric or fibrillar tau. The scFvs differentiate brain tissue homogenates of both 3×TG and tau-AD mice from wild-type mice, detecting oligomeric tau at much earlier ages than when neurofibrillary tangles are typically detected. The scFvs also distinguish human postmortem AD brain tissue from cognitively normal postmortem human brain tissue, demonstrating the potential of this approach for developing biomarkers for early detection and progression of AD.

Keywords: Alzheimer's disease; Antibody fragments; Biomarker; Brain tissue; Immunotherapy; Oligomeric tau; Phage display; Toxic tau aggregates; scFv.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / pathology
  • Animals
  • Antibodies / isolation & purification*
  • Biomarkers / analysis
  • Brain / metabolism*
  • Disease Models, Animal
  • Humans
  • Immunoglobulin Variable Region / immunology*
  • Immunoglobulin Variable Region / isolation & purification*
  • Mice, Transgenic
  • Peptide Library
  • Polymers
  • Protein Aggregates / immunology*
  • tau Proteins / analysis*
  • tau Proteins / immunology*
  • tau Proteins / toxicity

Substances

  • Antibodies
  • Biomarkers
  • Immunoglobulin Variable Region
  • Peptide Library
  • Polymers
  • Protein Aggregates
  • tau Proteins