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

12 Citations (Scopus)

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

Fingerprint

Synucleins
Immunotherapy
Poisons
Monoclonal Antibodies
Lewy Bodies
Lewy Body Disease
tau Proteins
Passive Immunization
Neurodegenerative Diseases
Parkinson Disease
Dopamine
Proteins
Phenotype
Injections
Antibodies
Brain
Therapeutics
Research

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Gerson, J. E., Farmer, K. M., Henson, N., Castillo-Carranza, D. L., Carretero Murillo, M., Sengupta, U., ... Kayed, R. (2018). Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy. Molecular Neurodegeneration, 13(1), [13]. https://doi.org/10.1186/s13024-018-0245-9

Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy. / Gerson, Julia E.; Farmer, Kathleen M.; Henson, Natalie; Castillo-Carranza, Diana L.; Carretero Murillo, Mariana; Sengupta, Urmi; Barrett, Alan; Kayed, Rakez.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 13, 15.03.2018.

Research output: Contribution to journalArticle

Gerson, JE, Farmer, KM, Henson, N, Castillo-Carranza, DL, Carretero Murillo, M, Sengupta, U, Barrett, A & Kayed, R 2018, 'Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy', Molecular Neurodegeneration, vol. 13, no. 1, 13. https://doi.org/10.1186/s13024-018-0245-9
Gerson JE, Farmer KM, Henson N, Castillo-Carranza DL, Carretero Murillo M, Sengupta U et al. Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy. Molecular Neurodegeneration. 2018 Mar 15;13(1). 13. https://doi.org/10.1186/s13024-018-0245-9
Gerson, Julia E. ; Farmer, Kathleen M. ; Henson, Natalie ; Castillo-Carranza, Diana L. ; Carretero Murillo, Mariana ; Sengupta, Urmi ; Barrett, Alan ; Kayed, Rakez. / Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy. In: Molecular Neurodegeneration. 2018 ; Vol. 13, No. 1.
@article{eba0902791964b6db1710317b649e360,
title = "Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy",
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",
author = "Gerson, {Julia E.} and Farmer, {Kathleen M.} and Natalie Henson and Castillo-Carranza, {Diana L.} and {Carretero Murillo}, Mariana and Urmi Sengupta and Alan Barrett and Rakez Kayed",
year = "2018",
month = "3",
day = "15",
doi = "10.1186/s13024-018-0245-9",
language = "English (US)",
volume = "13",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy

AU - Gerson, Julia E.

AU - Farmer, Kathleen M.

AU - Henson, Natalie

AU - Castillo-Carranza, Diana L.

AU - Carretero Murillo, Mariana

AU - Sengupta, Urmi

AU - Barrett, Alan

AU - Kayed, Rakez

PY - 2018/3/15

Y1 - 2018/3/15

N2 - 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.

AB - 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.

KW - Immunotherapy

KW - Neurodegeneration

KW - Oligomers

KW - Synucleinopathies

KW - Tau

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85043761395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043761395&partnerID=8YFLogxK

U2 - 10.1186/s13024-018-0245-9

DO - 10.1186/s13024-018-0245-9

M3 - Article

C2 - 29544548

AN - SCOPUS:85043761395

VL - 13

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 13

ER -