自组装多肽纳米管对APP/PS1转基因AD小鼠脑内不同Aβ聚集物的分型成像和靶向给药研究

The concentration and distribution of amyloid-β (Aβ) aggregates (e.g. oligomers, fibrils) are closely linked to the molecular pathology in Alzheimer’s disease (AD). Distinguish the different Aβ species with the imaging technology plays an important role for early-stage AD diagnosis. For AD therapy, inhibitors which can disaggregate toxic Aβ aggregates (oligomers and fibrils) in vitro can not specific target toxic Aβ species in brains, which result in some side effects. In this project, the self-assembled D-diphenylalanine peptide nonotubes will be modified with the Aβ specific antibodies (Aβ monomer antibody, Aβ oligomer antibody, Aβ fibril antibody). By loading cy5.5, the antibodies modified FF nanotubes can be used as a near-infrared fluorescent probe for distinguishing different Aβ species in APP/PS1 mouse brain. By loading inhibitor for Aβ toxic aggregates, the antibodies modified FF nanotubes can deliver the inhibitor to the specific Aβ aggregates. The mechanism of the improvement of congnitive abilites in APP/PS1 transgenic mouse by the targeting inhibitor delivery will be investigated with the Morris water-maze test and classification imaging of Aβ species in APP/PS1 mouse brain. This project will provide a new method for AD diagnosis and a nano-scaled targeting carrier for inhibitors to Aβ aggregates.

阿尔茨海默病（AD）的病程与AD病人脑内不同聚集形态的β-淀粉样多肽(Aβ)的含量和分布有着密切联系。实现活体脑内Aβ毒性聚集物的分型成像对AD早期诊断具有重要意义。AD的治疗研究中，针对Aβ毒性聚集物的解聚剂存在毒副作用大、靶向性不强的问题。本项目利用苯丙氨酸二肽（FF, D型氨基酸合成）自聚集纳米管为载体，在其表面分别修饰不同Aβ聚集物（单体、寡聚体、纤维）的抗体，使其具有靶向性。利用靶向FF纳米管负载cy5.5，在细胞、AD小鼠脑切片、AD小鼠活体层面，利用激光共聚焦显微镜和活体成像技术，实现靶向cy5.5-FF纳米管在APP/PS1转基因AD小鼠脑内对不同Aβ聚集物的分型成像；通过负载Aβ毒性聚集物解聚剂，实现AD小鼠脑内对不同Aβ聚集物的靶向给药。结合水迷宫实验评价靶向药物药效，并深入研究其作用机制。为AD诊断的活体成像研究提供新方法，为针对Aβ毒性聚集物的药物提供靶向纳米载体。

阿尔茨海默病（AD)的病程与AD病人脑内不同聚集形态的β-淀粉样多肽（Aβ）的含量和分布有着密切联系。实现活体脑内Aβ毒性聚集物的分型成像和靶向给药，筛选对AD小鼠症状有改善作用的化合物对AD早期诊断和治疗有着重要意义。本项目合成了表面修饰了Aβ不同聚集物抗体的靶向FF多肽纳米管，利用靶向FF纳米管包埋近红外染料cy5.5；利用自组装多肽水凝胶实现了生物活性物质的控制释放；研究了米糠黄酮对Aβ毒性聚集物诱导的神经细胞凋亡的抑制作用，及其对AD模型小鼠学习、记忆能力的改善作用和作用机理；利用计算机模拟技术筛选出对Aβ毒性聚集物有抑制作用的化合物，并利用细胞和AD模型小鼠实验验证其对神经细胞的保护作用和改善AD小鼠学习记忆能力的作用，并利用分子生物学方法研究了其作用机制。本项目的研究为药物/生物活性物质的控制释放提供了新的载体，为AD提供了新的潜在的治疗化合物。