IFN-γ Production by Amyloid β-specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer's Disease

J Immunol. 2013 Mar 1;190(5):2241-51. doi: 10.4049/jimmunol.1200947. Epub 2013 Jan 30.

Abstract

Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aβ-specific T cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aβ-specific CD4 T cells generated by immunization with Aβ and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Aβ deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Alzheimer Disease / immunology*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / immunology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / immunology
  • Animals
  • Antibodies / pharmacology
  • Brain / drug effects
  • Brain / immunology*
  • Brain / pathology
  • Cell Movement / drug effects
  • Disease Models, Animal
  • Gene Expression
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / immunology*
  • Microglia / pathology
  • Plaque, Amyloid / immunology
  • Plaque, Amyloid / pathology*
  • Presenilin-1 / genetics
  • Presenilin-1 / immunology
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th1 Cells / transplantation
  • Th17 Cells / immunology
  • Th17 Cells / pathology
  • Th17 Cells / transplantation
  • Th2 Cells / immunology
  • Th2 Cells / pathology
  • Th2 Cells / transplantation

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antibodies
  • Interleukin-17
  • Presenilin-1
  • Interferon-gamma