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Acta Neuropathologica

, Volume 136, Issue 1, pp 69–87 | Cite as

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

  • Brian Spencer
  • Sven Brüschweiler
  • Marco Sealey-Cardona
  • Edward Rockenstein
  • Anthony Adame
  • Jazmin Florio
  • Michael Mante
  • Ivy Trinh
  • Robert A. Rissman
  • Robert Konrat
  • Eliezer Masliah
Original Paper

Abstract

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

Tauopathy Pick’s disease Immunotherapy Alzheimer’s disease 

Notes

Acknowledgements

Supported by NIH grants AG5131, AG018440, AG051839. HEK293 antibody production was performed by the VBCF Protein Technologies Facility (www.vbcf.ac.at).

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Brian Spencer
    • 1
  • Sven Brüschweiler
    • 3
  • Marco Sealey-Cardona
    • 3
  • Edward Rockenstein
    • 1
  • Anthony Adame
    • 1
  • Jazmin Florio
    • 1
  • Michael Mante
    • 1
  • Ivy Trinh
    • 1
  • Robert A. Rissman
    • 1
    • 4
  • Robert Konrat
    • 3
  • Eliezer Masliah
    • 1
    • 2
    • 5
  1. 1.Department of NeurosciencesUniversity of CaliforniaSan DiegoUSA
  2. 2.Department of PathologyUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Computational and Structural BiologyUniversity of ViennaViennaAustria
  4. 4.Veterans Affairs San Diego Healthcare SystemSan DiegoUSA
  5. 5.Molecular Neuropathology Section, Laboratory of NeurogeneticsNational Institute on Aging, National Institutes of HealthBethesdaUSA

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