Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy

Mol Neurodegener. 2018 Mar 15;13(1):13. doi: 10.1186/s13024-018-0245-9.

Abstract

Background: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target.

Methods: We treated seven-month-old mice overexpressing mutated α-synuclein (A53T mice) with tau oligomer-specific monoclonal antibody (TOMA) and a control antibody and assessed both behavioral and pathological phenotypes.

Results: We found that A53T mice treated with TOMA were protected from cognitive and motor deficits two weeks after a single injection. Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice. Tau oligomer depletion also protected against dopamine and synaptic protein loss.

Conclusion: These results indicate that targeting tau oligomers is beneficial for a mouse model of synucleinopathy and may be a viable therapeutic strategy for treating diseases in which tau and α-synuclein have a synergistic toxicity.

Keywords: Immunotherapy; Neurodegeneration; Oligomers; Synucleinopathies; Tau; α-synuclein.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Brain / drug effects*
  • Brain / pathology
  • Humans
  • Immunization, Passive
  • Immunotherapy / methods*
  • Mice
  • Mice, Transgenic
  • Parkinson Disease / pathology
  • alpha-Synuclein*
  • tau Proteins / antagonists & inhibitors*

Substances

  • Antibodies, Monoclonal
  • alpha-Synuclein
  • tau Proteins