Toxoplasma gondii drives myeloid immune cell recruitment to amyloid plaques in Alzheimer's model mice.

Abstract

Infections in the central nervous system result in immune cell trafficking into the brain and microglial activation, which may influence Alzheimer's Disease neuropathology. Toxoplasma gondii infection induces a robust neuroimmune response and a reduction in amyloid plaques in the brains of Alzheimer's model mice. We investigated the myeloid cell response in the immediate vicinity of amyloid plaques in the brain by injecting 3-month-old 5xFAD mice with T. gondii or PBS as a control. T. gondii chronic infection (6 weeks) resulted in reduced amyloid plaque area, volume, and intensity in the cortex, and plaques with decreased circularity based on 6E10 and Thio-S staining. The brains of T. gondii-infected mice also had increased AIF1, AXL, and CLEC7A transcripts for disease-associated microglia (DAM), and elevated IBA1, MAC2, and CD68 phagolysosomal colocalization with amyloid, indicating myeloid cell activation around plaques. CD4 and CD8 T cells were also increased near amyloid and IBA1cells in T. gondii-infected mice. To determine the extent of peripheral myeloid cell recruitment to amyloid, bone marrow from CAG-CFP mice was transplanted into irradiated, head-shielded 5xFAD mice prior to infection. Cyancells were found surrounding plaques in the brains of T. gondii-infected mice and were comprised predominantly of Ly6Cpatrolling monocytes, followed by Ly6Cinflammatory monocytes and T cells. In addition, the majority of myeloid cells and T cells recruited to the brain were derived from skull bone marrow. These data demonstrate that T. gondii infection increases the infiltration of monocytes and T cells from the skull bone marrow niche and the recruitment of highly activated myeloid cells surrounding amyloid plaques in the brains of 5xFAD mice.