Lambracht-Washington Doris, Rosenberg Roger N
Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Immunotargets Ther. 2013 Aug 1;2013(2):105-114. doi: 10.2147/ITT.S31428.
Immunotherapy might provide an effective treatment for Alzheimer disease (AD). A unique feature of AD immunotherapies is that an immune response against a self antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focussed on two possible targets in this regard: One is the inhibition of accumulation and deposition of Amyloid beta 1-42 (Aβ42), which is one of the major peptides found in senile plaques and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations) is already in several stages of clinical trials, tau based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phoshorylated tau was found, high interest has again focussed on further development of tau based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. And last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects as these two pathologies are likely synergistic; an approach which has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, present on overview on halted, ongoing and upcoming clinical trials together with ongoing preclinical studies targeting tau or Aβ42.
免疫疗法可能为阿尔茨海默病（AD）提供有效的治疗方法。AD免疫疗法的一个独特之处在于，需要引发针对自身抗原的免疫反应，同时又不引起不良的自身免疫反应。目前的研究集中在这方面的两个可能靶点：一是抑制淀粉样β1-42（Aβ42）的积累和沉积，Aβ42是在老年斑中发现的主要肽段之一；另一个靶点是过度磷酸化的tau蛋白，它在神经细胞内形成神经原纤维缠结，并与痴呆症的进展相关。小鼠模型表明，用相应的抗Aβ或抗tau抗体靶向Aβ42和tau的免疫疗法可以使这些小鼠有显著改善。虽然抗Aβ免疫疗法（主动和被动免疫）已处于临床试验的几个阶段，但基于tau的免疫疗法仅在小鼠模型中进行了分析。最近，由于发现痴呆症进展与磷酸化tau水平之间存在显著相关性，人们再次高度关注基于tau的疗法的进一步开发。虽然Aβ免疫疗法可能会延迟AD的发病，但靶向tau的免疫疗法可能在该疾病的后期阶段带来益处。最后但同样重要的是，同时用免疫疗法靶向Aβ和tau可能会提供额外的治疗效果，因为这两种病理可能具有协同作用；这一方法尚未经过测试。在这篇综述中，我们将总结用于测试AD可能疗法的动物模型、关于Aβ42和tau生物学的一些事实，概述已停止、正在进行和即将进行的临床试验，以及针对tau或Aβ42的正在进行的临床前研究。
