Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer’s disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.

tau 蛋白的病理性聚集体在神经退行性 tauopathies 的大脑中积累，包括阿尔茨海默病和额颞叶变性 (FTLD-tau)。尽管针对 tau 的这些疾病的免疫疗法正在出现，但鼻腔给药比传统的疫苗接种方法具有许多好处，但对 tau 蛋白病变是否有效尚不清楚。在这里，我们开发了针对与 FTLD-tau 相关的病理性 tau 分泌形式的疫苗接种，使用仙台病毒 (SeV) 载体感染宿主鼻粘膜，这是免疫系统的关键部分。作为滴鼻剂给予的 Tau 疫苗诱导组织 tau 免疫反应性抗体的产生并改善 FTLD-tau 模型小鼠的认知障碍。体内成像和死后神经病理学分析表明，免疫小鼠海马体中磷酸化 tau 积累、神经毒性神经胶质增生和神经元丢失受到抑制。这些发现表明，鼻腔疫苗递送可能为广泛的人类 tau 蛋白病患者提供治疗机会。