Aß3-10-KLH疫苗免疫防治Alzheimer病(AD)的机制探讨

With regard to the immunotherapies of Alzheimer Disease(AD), the optimal may lie to the active immunotherapy with considerable therapeutic effects and no significant side effects. Most clinical researches concerning the immunotherapy of AD finally ended in failure,considering the antibodies of these researches, they all binded to full length Aβ1-42 monomer, with some also to oligomers and senile plaque, and some to the senile plaque only. Recent researches have demonstrated that the optimal immunotherapy is that antibody bind to the oligomers and senile plaque, with no specificity to the Aβ1-42 monomer. Vaccine based on Aβ3-10 we constructed has been studied systemically with considerable and consistent effects and no significant side effects. Particularly, our previous studies have found its advantages in clearing the soluble Aβ, and then preliminary experiment results showed no recognition to the Aβ1-42, suggesting a probable targetting on oligomers. Therefore, we intent to investigate whether the vaccine based on Aβ3-10 mainly eliminate oligomers, which type of oligomers to be cleared, how oligomer clearance correlates with senile plaque, especially the vascular Aβ deposition, and microhemorrhage, whether to recognize monomers like AβpE3-X if not to recognize Aβ1-42, and how about the sustainability of the effect and so on. This vaccine will be the optimal one if the hypothesis has been proven, and may provide new ideas toward researches of better vaccines and illumination of the pathogenesis of AD.

Alzheimer病(AD)免疫治疗最理想的是主动免疫、效果好且无明显副作用，目前临床研究的AD免疫治疗多以失败为告终，分析其特征是抗体均结合Aß1-42等单体或同时结合Aß1-42等单体、寡聚体和老年斑或只结合老年斑。近来的研究表明AD免疫治疗的理想是抗体结合寡聚体可同时结合老年斑但不应该结合Aß1-42单体。我们构建的基于Aß3-10的疫苗经系统研究具效果好、作用持续且无明显副作用，特别是前期研究发现其优势与其清除可溶性Aß有关，预实验结果提示其抗体不识别Aß1-42，说明该免疫的主要靶点很可能是寡聚体，因此立项予以探讨基于Aß3-10的疫苗免疫是否主要清除寡聚体；清除何种类型寡聚体,寡聚体的清除与老年斑特别是脑血管Aß沉积及微出血有何关联；是否识别AßpE3-X等单体；疗效的持续性如何等。如果证明假设成立则该疫苗将是目前最理想的疫苗，为开发更好的疫苗及阐明AD发生机制提供依据

尽管Alzheimer病（AD）的发病率逐渐升高，但一直无有效的治疗方法。近年来针对AD发生的Aß学说的研究表明Aß寡聚体是AD发生的关键，开发特异性靶向并减少Aß寡聚体的药物对AD的防治具重要意义，以Aß3-10-KLH为抗原对其免疫防治Alzheimer病(AD)的机制进行了探讨，结果表明Aß3-10为抗原产生的抗体（7B8）对Aß单体的亲和能力低，具有能保留部分游离的Aß单体发挥其生理功能并清除过多的Aß单体减少寡聚体的形成，同时又具有清除已形成的不同类型和大小寡聚体包括焦谷氨酸化肽段AßpE3-42形成的寡聚体的作用及能够清除老年斑，则具备了目前临床试验中靶向寡聚体并显示有疗效药物的所有优点并弥补其不足，以AD转基因鼠的研究表明该抗体改善认知、保护神经元且副作用少，在此基础上我们对该抗体申请了国家发明专利，对AD防治药物的研发具重要指导意义。