NinTenDo

Alzheimer's disease (AD) is a multifactorial disease for which several molecular and functional abnormalities are now well known. Among these, neuronal excitotoxicity on neurons leads to synaptic loss and build-up of DNA double-strand breaks (DSB) that drive neurodegeneration and cognitive decline. A role for adaptative immunity, and inflammation due to chronically activated microglia has been suggested as a trigger and regulator of AD, but the neuroimmune interplay that underlies neuronal excitotoxicity and dysfunction remains ill-defined and is certainly diverse. As a common neurotropic brain-persisting pathogen, which infection is tightly controlled by specific immune responses, the parasite Toxoplasma gondii (Tg) may impact on the progression of AD. Supporting this hypothesis, our interdisciplinary consortium has gathered preliminary data showing aggravation of Tau pathology, inflammation dominated by Il-1b signaling and earlier onset of cognitive decline in models of Tauopathy or amyloidosis infected by latent Tg. We have also shown the instrumental role of DSB on spatial memory deficits promoted by Tg. In our project NinTenDo, our overarching goal is to decipher the molecular mechanisms and determinants that promote the progression of AD pathology in the brain of two Tg-infected transgenic mouse strains, modeling the two major lesional determinants of AD, i.e., tauopathy and amyloidogenesis. Our specific aims will be i) to identify specific neuro-immune signatures induced by chronic Tg infection in AD brains, with specific correlation with AD outcome progression; ii) to evaluate the specific contribution of neuronal vs. microglial IL-1b signaling to Tg-induced progression of AD pathology. Overall, this project will allow to decipher mechanisms that may link AD to pathogen persistence in the brain, and will improve our understanding on new regulatory mechanisms of neuro-immune pathophysiology of cognitive decline.