Richter Monique, Mewes Agneta, Fritsch Manuela, Krügel Ute, Hoffmann Ralf, Singer David
Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Deutscher Platz 5, Leipzig 04103, Germany.
Center for Biotechnology and Biomedicine (BBZ), Universität Leipzig, Deutscher Platz 5, Leipzig 04103, Germany.
Vaccines (Basel). 2014 Jul 29;2(3):601-23. doi: 10.3390/vaccines2030601.
Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235) and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer's disease (AD) specific B cell epitopes with foreign (bacterial) T cell epitopes induced fast immune responses with high IgG₁ titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.
细胞内神经原纤维缠结和细胞外老年斑是主动和被动免疫疗法的潜在靶点。在本研究中，我们使用转基因小鼠模型P301S进行主动免疫，所用肽疫苗由双磷酸化tau新表位（pSer202/pThr205、pThr212/pSer214、pThr231/pSer235）和来自破伤风毒素或结核抗原Ag85B的免疫调节性T细胞表位组成。重要的是，设计的疫苗将阿尔茨海默病（AD）特异性B细胞表位与外来（细菌）T细胞表位相结合，在预防性免疫后诱导了快速免疫反应，IgG₁滴度较高，随后在观察期内下降。通过评估动物行为以及采用生化和组织化学技术评估大脑病理来调查免疫效果。免疫小鼠的存活时间明显延长，瘫痪程度减轻，优于安慰剂处理的小鼠。此外，它们在20周龄时的转棒试验和横梁行走试验中表现明显更好，表明疾病发展有所减缓。48周龄的接种疫苗小鼠在横梁行走试验中的表现明显优于对照动物，这与存活率的提高一起无疑证明了治疗效果。总之，数据提供了有力证据，表明主动免疫疗法可以降低AD中形成的沉积物的毒性作用。
