Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease.
Vaccination against amyloid beta-peptide (Abeta) has been shown to be successful in reducing Abeta burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Abeta immunization did not show T cell infiltrates in the brain of these mice, an Abeta vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Abeta-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Abeta-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. Moreover, we show that a single immunization with the dominant T cell epitope Abeta10-24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-gamma under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Abeta plaques in the brain and were associated with clearance of Abeta. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Abeta. Using primary cultures of microglia, we show that IFN-gamma enhanced clearance of Abeta, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-gamma in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Abeta immunization and provides a model to investigate both the beneficial and detrimental effects of Abeta-specific T cells.
Monsonego
Alon
A
National Institute of Biotechnology and Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel.
Imitola
Jaime
J
Petrovic
Sanja
S
Zota
Victor
V
Nemirovsky
Anna
A
Baron
Rona
R
Fisher
Yair
Y
Owens
Trevor
T
Weiner
Howard L
HL
D000544:Alzheimer Disease / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007114:Immunization; D007125:Immunogenetics; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008590:Meningoencephalitis / Q000139:chemically induced* / Q000150:complications / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D016229:Amyloid beta-Peptides; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D007371:Interferon-gamma