IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease.
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.
Trinity College Institute of Neuroscience, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Tara C
TC
Browne
Keith
K
McQuillan
Róisín M
RM
McManus
Julie-Ann
JA
O'Reilly
Kingston H G
KH
Mills
Marina A
MA
Lynch
D019264:Adoptive Transfer; D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000276:immunology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D058225:Plaque, Amyloid / Q000276:immunology / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D020381:Interleukin-17; D053764:Presenilin-1; D007371:Interferon-gamma