Background: Tangle pathology (hyperphosphorylated and aggregation of tau) is a major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Increasing evidence suggests that inflammatory processes in the brain precede tau pathology. A previous study from our group has demonstrated that enhancing neuroinflammation either via a Toll-Like Receptor-4 (TLR-4) ligand lipopolysaccharide (LPS) or genetic ablation of the Cx3cr1 (fractalkine receptor) led to increased tau phosphorylation, aggregation and working memory impairment in a manner dependent upon the activation of interleukin-1 receptor (IL-1R)-p38 mitogen activated protein kinase (p38 MAPK) pathway.  Aims and methods: To block IL-1R and TLR-4 receptor signaling, we targeted and performed cell-specific deletion of MyD88 - a common adapter protein of IL-1 and TLR-4 receptors using Cre-LoxP technology. Results and conclusions: First, in contrast to what was expected, microglia-restricted deletion of MyD88 (in CD11bCreMyD88^f/f mice) led to enhanced AT8- and AT180-site tau phosphorylation. Notably, this effect was exacerbated upon LPS administration, suggesting the MyD88 may be required for homeostasis of tau. Second, infiltration of CD45+ peripheral monocytes was increased within the brains of CD11bCreMyD88^f/f mice compared to MyD88^f/f mice. Third, gene expression analysis comparing the CD11bCreMyD88^f/f to MyD88^f/f suggested alterations in key inflammatory cytokines. Finally, neuronal-restricted deletion of MyD88 in hTau mouse model of tauopathy (hTau-Mapt^-/-/CamKIIαCreMyD88^f/f) showed drastic reduction in the levels of truncated neurotoxic tau in the cortex of hTauMapt^-/-/CamKIIαCreMyD88^f/f mice compared to hTauMapt^-/- mice, suggesting neuron-restricted deletion of MyD88 is neuroprotective. Further studies on the characterization of truncated tau species and the effect of hTau on microglia-restricted (CD11b) deletion of MyD88 on tangle pathology and cognitive function are ongoing.