Truncated tau modulates neuron-glia signaling through CX3CL1-CX3CR1 and CD47-SIRP-α pathways.

Tauopathies encompass a group of disorders characterized by abnormal accumulation of tau protein into neurofibbrilary pathology and neuroinflammation. Understanding how glial cells interact with neurons is important to unraveling the complex mechanisms driving the progression of tauopathies. In this study, we established a multi-component cellular model for tauopathies comprising neuronal cells inducible expressing pathological truncated tau, primary microglia, and astrocytes. We successfully identified optimal culture conditions, with 1% serum supplemented with B27 proving to be most effective in enhancing neuronal protein expression, tau levels, and cell viability. This condition supported improved neuronal differentiation and synaptic marker expression, reflecting a more robust neuronal phenotype compared to monocultures. The increase in pro-inflammatory cytokines production underscores the model's capability to replicate the inflammatory environment characteristic of neurodegenerative diseases. Importantly, we observed that truncated tau significantly modulates key signalling pathways, notably the CX3CL1-CX3CR1 and CD47-SIRP-α pathways. We found that pathological changes in tauopathies altered neuron-glia interactions, leading them towards a more quiescent glial state.The alterations in signaling were accompanied by changes in tau phosphorylation, with neuroinflammation exacerbating hyperphosphorylation of truncated tau, while minimally affecting endogenous tau. In conclusion, our study highlights that pathological truncated tau significantly affects the expression of membrane-anchored fractalkine. This differential modulation, coupled with changes in inflammatory conditions, suggests that early-stage tau pathology can influence neuroinflammatory responses and may still allow neuronal cells to engage in protective mechanisms.