Chronic latent Toxoplasma gondii infection precipitates cognitive decline in an inducible Alzheimer's disease model

Neuroimmune dysregulations strongly contribute to the pathophysiology of Alzheimer's Disease (AD). Because pathogens shape the immune system over lifetime, their association with AD has been suggested. Increasing evidence supports a role for the prevalent, brain-persisting parasite Toxoplasma gondii (Tg) in chronic neurological diseases. Yet, the contribution of Tg chronic infection on AD clinical progression and pathogenesis remains unexplored. Considering the temporal relationship between natural Tg infection and AD occurrence, it seems legitimate to evaluate the effects of a seemingly silent strain of Tg, on the later development of AD. To tackle this question, we combined infection by transgenic Tg (Tg.GRA6-OVA), which results in a persisting and subclinical infection, with an inducible mouse model of AD amyloidosis, the TetO-APPSweInd mouse (ihAPP), in which amyloid- peptide production and deposition, can be induced upon removal of doxycycline treatment. Mice were kept on doxycycline-dosed chow until chronic latent Tg infection is established. Behavioral, immune and biochemical analysis were performed after doxycycline withdrawal.We found that Tg-infected ihAPP mice (Tg-ihAPP), displayed cognitive deficits earlier than non-infected AD mice (NI-AD), including impaired object recognition memory and spatial learning and memory deficits. NI-ihAPP mice are impaired in these tasks only 2 months later. Interestingly, Tg-ihAPP mice had less β-amyloid plaques in the cortex and hippocampus compared to NI-AD, confirming previous findings. Facs analyses of brain-isolated cells revealed unique changes in monocytes and CD8+ T cells in Tg-ihAPP mice compared to the other groups.Together, our data shed light on novel neuroimmune mechanisms at play in AD progression.