Aβ-induced meningoencephalitis is IFN-γ-dependent and is associated with T cell-dependent clearance of Aβ in a mouse model of Alzheimer's disease

Vaccination against amyloid β-peptide (Aβ) has been shown to be successful in reducing Aβ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Aβ immunization did not show T cell infiltrates in the brain of these mice, an Aβ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Aβ-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Aβ-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 Aβ10-24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-γ under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Aβ plaques in the brain and were associated with clearance of Aβ. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Aβ. Using primary cultures of microglia, we show that IFN-γ enhanced clearance of Aβ, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-γ in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Aβ immunization and provides a model to investigate both the beneficial and detrimental effects of Aβ-specific T cells.