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

Julia E. Gerson, Kathleen M. Farmer, Natalie Henson, Diana L. Castillo-Carranza, Mariana Carretero Murillo, Urmi Sengupta, Alan Barrett, Rakez Kayed

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Article number13
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Mar 15 2018

Keywords

  • Immunotherapy
  • Neurodegeneration
  • Oligomers
  • Synucleinopathies
  • Tau
  • α-synuclein

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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