Profiling the impact of different tau species on glial cell biology.

Our findings reveal that different patterns of tau accumulation elicit fundamentally distinct glial responses. Insoluble tau deposition (P301L) primarily triggers microglial inflammatory pathways without substantial metabolic disruption, suggesting a direct response to tau fibrils. In contrast, soluble tau species (A152T) impact multiple cellular mechanisms simultaneously, including metabolic function, calcium homeostasis, and phagocytosis, potentially explaining the neuronal loss previously observed in this model. These distinct cellular signatures expand our understanding of how tau contributes to neurodegeneration and may inform more targeted therapeutic strategies based on predominant patterns of tau accumulation in different tauopathies.