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.

包括额颞叶痴呆（FTD）和阿尔茨海默氏病（AD）在内的刀伤病是临床上以认知能力下降为特征的进行性神经退行性疾病，可能是由于神经元内神经原纤维缠结（NFT）的过度磷酸化病理性tau（pTau）聚集所引起。当前，尚无FDA批准的可治愈，减慢或预防关节病的治疗方法。当前针对pTau的免疫疗法策略已经产生了令人鼓舞的数据，但可能引起对可扩展性，可负担性和功效的担忧。在这里，我们设计了一种基于病毒样颗粒（VLP）的疫苗，其中在苏氨酸181处磷酸化的tau肽与Qß噬菌体VLP（pT181-Qß）高价连接。我们证明，用pT181-Qß进行疫苗接种足以在Non-Tg和rTg4510小鼠的血清和大脑中诱导强大而长寿的抗pT181抗体应答。在人类FTD和AD死后脑切片中，仅来自接种pT181-Qß的小鼠的血清对经典的树突状pTau具有反应性。最后，我们证明pT181-Qß疫苗可减少海马和皮层中高磷酸化pTau的可溶和不可溶物种，避免Th1介导的促炎细胞反应，防止海马和call体萎缩，并在4个月内挽救认知功能障碍FTD的旧rTg4510小鼠模型。这些研究为开发以VLP为基础的针对pTau的免疫疗法并潜在预防阿尔茨海默氏病和相关疾病提供了有效的科学前提。