Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes

Introduction: Alzheimer's disease (AD) is associated with the accumulation of beta-amyloid (A beta) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated A beta peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD. Results: Chronic infection with T. gondii was associated with reduced A beta and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2(hi) Ly6C(hi) monocytes, CCR2(+) Ly6C(int), and CCR2(+) Ly6C(low) mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of A beta ex vivo. The F4/80(+) Ly6C(low) macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2(+) Ly6C(hi) monocytes resulted in an increased amount of A beta in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits beta 1i/LMP2, beta 2i/MECL-1, and beta 5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic A beta degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of A beta clearance. Conclusions: Our results indicate that chronic Toxoplasma infection ameliorates beta-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6C(hi) monocytes and by enhancement of phagocytosis and degradation of soluble A beta. Our findings provide evidence for a modulatory role of inflammation-induced A beta phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD.