基于乙肝核心 VLP 的错误折叠 tau 疫苗可诱发强烈免疫应答，并改善 Tau.P301S 阿尔茨海默病和额颞叶痴呆小鼠模型的认知缺陷和神经病理学进展。
Hepatitis B core VLP-based mis-disordered tau vaccine elicits strong immune response and alleviates cognitive deficits and neuropathology progression in Tau.P301S mouse model of Alzheimer's disease and frontotemporal dementia.
机构信息
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
出版信息
Alzheimers Res Ther. 2018 Jun 19;10(1):55. doi: 10.1186/s13195-018-0378-7.
BACKGROUND
Truncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). Tau, an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau-targeted approach may have beneficial effects in the treatment of AD and FTD.
METHODS
In this study, we genetically fused tau epitope to the hepatitis B virus core protein (HBc) major immunodominant region (MIR) (with the resultant protein termed T294-HBc), and we subcutaneously immunized a Tau.P301S transgenic mouse model of FTD and AD with T294-HBc four times. The levels and characteristics of antibodies induced by T294-HBc were determined by enzyme-linked immunosorbent assay. The effect of T294-HBc on the cognitive deficits of Tau.P301S mice was tested using the Morris water maze test, novel object recognition, and a Y-maze test. Western blot analysis and IHC were applied to measure the effect of T294-HBc on tau pathologies and neuroinflammation in the mouse brains.
RESULTS
The results showed that T294-HBc self-assembled into HBc chimeric virus-like particles (VLPs) with tau displayed on the surface and that it induced high antibody titers specifically against the mis-disordered truncated tau. Further investigation showed that these antibodies simultaneously bound to microtubule-binding regions 1-4 (MTBR1-4) [tau tau, tau, tau and tau(P301S)]. Moreover, T294-HBc VLP vaccination significantly ameliorated memory and cognitive decline; reduced the levels of AT8-positive tau, truncated tau monomer, and oligomer; attenuated microgliosis and astrogliosis; and rescued synaptic deficits in Tau.P301S transgenic mice.
CONCLUSIONS
T294-HBc VLP vaccine elicited strong immune response and alleviated cognitive deficits and neuropathology progression in Tau.P301S mice, indicating that the T294-HBc VLP vaccine has promising therapeutic potential for the treatment of AD and FTD.
背景
截断的异常 tau 蛋白在阿尔茨海默病（AD）和额颞叶痴呆（FTD）的发病机制中起着重要作用。tau 是截断 tau 中的一个表位，对于病理性 tau-tau 相互作用和聚集至关重要。针对 tau 的方法可能对 AD 和 FTD 的治疗有有益的效果。
方法
在这项研究中，我们将 tau 表位基因融合到乙型肝炎病毒核心蛋白（HBc）主要免疫显性区（MIR）（得到的蛋白称为 T294-HBc），并用 T294-HBc 对 FTD 和 AD 的 Tau.P301S 转基因小鼠模型进行了四次皮下免疫。通过酶联免疫吸附试验测定 T294-HBc 诱导的抗体的水平和特性。使用 Morris 水迷宫测试、新物体识别和 Y 迷宫测试测试 T294-HBc 对 Tau.P301S 小鼠认知缺陷的影响。应用 Western blot 分析和免疫组化来测量 T294-HBc 对小鼠大脑中 tau 病理和神经炎症的影响。
结果
结果表明，T294-HBc 自组装成 HBc 嵌合病毒样颗粒（VLPs），表面展示 tau，诱导针对异常截断 tau 的高抗体滴度。进一步的研究表明，这些抗体同时结合微管结合区 1-4（MTBR1-4）[tau tau、tau、tau 和 tau（P301S）]。此外，T294-HBc VLP 疫苗接种显著改善了记忆和认知下降；降低了 AT8 阳性 tau、截断单体 tau 和寡聚物的水平；减弱了小胶质细胞和星形胶质细胞的激活；并挽救了 Tau.P301S 转基因小鼠的突触缺陷。
结论
T294-HBc VLP 疫苗引起了强烈的免疫反应，减轻了 Tau.P301S 小鼠的认知缺陷和神经病理学进展，表明 T294-HBc VLP 疫苗具有治疗 AD 和 FTD 的潜在治疗前景。
Zotero 插件