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 beta-peptide (A beta) has been shown to be successful in reducing A beta burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although A beta immunization did not show T cell infiltrates in the brain of these mice, an A beta vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of A beta-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong A beta-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 A beta 10-24 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 A beta plaques in the brain and were associated with clearance of A beta. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with A beta. Using primary cultures of microglia, we show that IFN-gamma enhanced clearance of A beta, 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 A beta immunization and provides a model to investigate both the beneficial and detrimental effects of A beta-specific T cells.