Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

Acta Neuropathol. 2018 Jul;136(1):69-87. doi: 10.1007/s00401-018-1869-0. Epub 2018 Jun 14.


Alzheimer's disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of β-amyloid (Aβ) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40-62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal-lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick's Disease.

Keywords: Alzheimer’s disease; Immunotherapy; Pick’s disease; Tauopathy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Animals
  • Apolipoproteins B / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line, Transformed
  • Coculture Techniques
  • DNA Repeat Expansion / genetics*
  • Disease Models, Animal
  • Exploratory Behavior / drug effects
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Neuroblastoma / pathology
  • Phosphorylation
  • Pick Disease of the Brain / drug therapy*
  • Pick Disease of the Brain / genetics
  • Pick Disease of the Brain / pathology
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Single-Chain Antibodies / therapeutic use*
  • rab5 GTP-Binding Proteins / metabolism
  • tau Proteins / genetics*
  • tau Proteins / immunology*
  • tau Proteins / metabolism


  • Apolipoproteins B
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Single-Chain Antibodies
  • tau Proteins
  • rab5 GTP-Binding Proteins