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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; 190(5):2241-51JI

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.

Authors+Show Affiliations

Trinity College Institute of Neuroscience, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23365075

Citation

Browne, Tara C., et al. "IFN-γ Production By Amyloid Β-specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer's Disease." Journal of Immunology (Baltimore, Md. : 1950), vol. 190, no. 5, 2013, pp. 2241-51.
Browne TC, McQuillan K, McManus RM, et al. 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;190(5):2241-51.
Browne, T. C., McQuillan, K., McManus, R. M., O'Reilly, J. A., Mills, K. H., & Lynch, M. A. (2013). IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. Journal of Immunology (Baltimore, Md. : 1950), 190(5), pp. 2241-51. doi:10.4049/jimmunol.1200947.
Browne TC, et al. 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. PubMed PMID: 23365075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. AU - Browne,Tara C, AU - McQuillan,Keith, AU - McManus,Róisín M, AU - O'Reilly,Julie-Ann, AU - Mills,Kingston H G, AU - Lynch,Marina A, Y1 - 2013/01/30/ PY - 2013/2/1/entrez PY - 2013/2/1/pubmed PY - 2013/4/6/medline SP - 2241 EP - 51 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 190 IS - 5 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/23365075/IFN_γ_Production_by_amyloid_β_specific_Th1_cells_promotes_microglial_activation_and_increases_plaque_burden_in_a_mouse_model_of_Alzheimer's_disease_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=23365075 DB - PRIME DP - Unbound Medicine ER -