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), but the etiology of AD remains ill-defined and is certainly diverse. Because pathogens shape the immune system over lifetime, their association with AD have been suggested. Increasing evidence supports a role for the prevalent, brain-persisting parasite Toxoplasma gondii (Tg) in chronic neurological diseases. Yet, overall, our current knowledge about the impact of chronic Tg infection on AD pathology and clinical progression remains sparse. There have been limited attempts to describe the impact of Tg infection on neuropathological lesions in AD mouse models. Up to now, the consequences of latent Tg infection on the severity and progression of cognitive decline and on the neuroimmune landscape, as well as the underlying molecular mechanisms, remain ill-defined.

Considering the temporal relationship between natural Tg infection and AD occurrence, it seems legitimate to evaluate the effects of a strain of Tg which is effectively controlled and result in latent infection, on the later development of AD. To tackle this question, we combined infection by transgenic Tg expressing a model antigen (Tg.GRA6-OVA) that is efficiently presented by MHC I in C57BL/6 mice and results in a CD8+ T cell-controlled persisting and latent infection, with an inducible mouse model of AD amyloidosis, the TetO-APPSweInd mouse (ihAPP), in which amyloid-β 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 indicate that preexistent and in appearance silent chronic Tg infection may hasten the progression of cognitive decline in AD while contributing to Aβ plaques nibbling and involving neuroimmune mechanisms.