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Hyperphosphorylated tau (p-tau) forms neurofibrillary tangles, a hallmark of Alzheimer's disease (AD) and related tauopathies, yet tangles alone are insufficient to cause neuronal dysfunction or death. Tau isolated from AD brains induces pathological deposits in non-transgenic mice but minimal cognitive decline, leaving the neurotoxic tau species unclear. Here, we show that intrahippocampal injection of recombinant soluble p-tau oligomers in wild-type mice induces progressive cognitive deficits and tauopathy spreading from the hippocampus to the cortex and contralateral hemisphere. This pathology accelerates in PS19 mice expressing full-length human tau (1N4R) with the P301S mutation and is mitigated by apomorphine, an inhibitor of p-tau aggregation. Using CCR2-CreER;R26R-GFP mice, we traced monocyte infiltration and found robust activation of SYK-coupled C-type lectin receptor (CLR) signaling after p-tau injection, but not with nonphosphorylated tau. CCR2 knockout reduced tau spread and improved cognition, while pharmacological SYK inhibition or monocyte-specific knockdown suppressed monocyte-mediated transmission and rescued behavior. These findings suggest that inflammatory monocytes promote p-tau transmission via SYK-coupled CLR signaling, highlighting them as potential therapeutic targets in AD.