CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia (DAM) states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of Alzheimer's disease. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations. Sample of WT mouse whole brain (pool of 4 whole brains) (WT), sample of 5xFAD mouse whole brain (pool of 4 whole brains) (5xFAD), sample of 5xFAD x PS19 and Tau seed injected mouse whole brain (pool of 4 hemispheres ipsilateral of the Tau-seed injection) (5xFAD_T_Ts_Ipsilateral), sample of 5xFAD x PS19 and Tau seed injected mouse whole brain (pool of 4 hemispheres contralateral of the Tau-seed injection) (5xFAD_T_Ts_Contralateral), sample of 5xFAD x PS19 and Tau seed injected mouse whole brains treated with PLX3397 (pool of 2 whole brains) (5xFAD_T_Ts_PLX), sample of 5xFAD x PS19 and Tau seed injected mouse control untreated whole brains (pool of 2 whole brains) (5xFAD_T_Ts_CTRL)