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Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are progressive neurodegenerative diseases clinically characterized by cognitive decline and could be caused by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles (NFTs) inside neurons. There is currently no FDA-approved treatment that cures, slows or prevents tauopathies. Current immunotherapy strategies targeting pTau have generated encouraging data but may pose concerns about scalability, affordability, and efficacy. Here, we engineered a virus-like particle (VLP)-based vaccine in which tau peptide, phosphorylated at threonine 181, was linked at high valency to Qß bacteriophage VLPs (pT181-Qß). We demonstrate that vaccination with pT181-Qß is sufficient to induce a robust and long-lived anti-pT181 antibody response in the sera and the brains of both Non-Tg and rTg4510 mice. Only sera from pT181-Qß vaccinated mice are reactive to classical somatodendritic pTau in human FTD and AD post-mortem brain sections. Finally, we demonstrate that pT181-Qß vaccination reduces both soluble and insoluble species of hyperphosphorylated pTau in the hippocampus and cortex, avoids a Th1-mediated pro-inflammatory cell response, prevents hippocampal and corpus callosum atrophy and rescues cognitive dysfunction in a 4-month-old rTg4510 mouse model of FTD. These studies provide a valid scientific premise for the development of VLP-based immunotherapy to target pTau and potentially prevent Alzheimer’s diseases and related tauopathies., Tauopathies: Active vaccination of mouse tauopathy Tauopathies such as fronto-temporal dementia or Alzheimer’s disease are characterized by the accumulation of phosphorylated Tau (pTau) protein into pathogenic neurofibrillary tangles (NFT). Kiran Bhaskar and colleagues at the University of New Mexico investigate the efficacy of an active vaccine approach in the treatment of rTg4510 mice—an aggressive model of tauopathy. Mice receive 3 intramuscular doses of a disease-relevant pTau peptide (pT181) multivalently conjugated to an immunostimulatory bacteriophage virus-like particle (pT181-Qß). Vaccination induces high titers of anti-pTau—stable to at least 20 weeks—that is also able to bind human disease samples, but importantly does not react to unphosphorylated physiological Tau protein. Antibody can enter the brain and bind both soluble and intraneuronal pTau. Vaccination of mice reduces brain NFT, pathology, indicators of neuroinflammation and improves cognitive function in two different models of memory.