Multiple Approaches to ABeta Vaccination in Animal Mode*

描述（申请人提供）：APP转基因的开发 (APP/Tg）的阿尔茨海默病（AD）小鼠模型提供了有价值的 一种实验系统，在其中测试关于潜在机制的假设 AD的发病和进展，以及潜在的治疗方法。 Schenk等人的初步报告，连同最近的出版物， 证明用纤维状A β 1 -42免疫APP/Tg小鼠 （Abeta 42）肽阻断了沉积，并启动了现有的 从大脑中沉淀出来。此外，已确定抗Abeta 抗体可以保护小鼠免受阿尔茨海默病样记忆丧失的影响。 然而，关于联合国的作用， Abeta的细胞免疫应答，Abeta清除机制， 自身免疫反应，以及与预期变异性相关的问题， 由MHC的高度多态性引起的免疫反应。 用Abeta肽免疫的成本、安全性和有效性都是 必须仔细评估的关键因素，以制定一个 成功的疫苗理想的Abeta疫苗应该针对免疫反应 对清除至关重要的Abeta免疫原性表位， 这些抗体可能导致不希望的副作用。 因此，本提案的目标是：㈠广泛审查 初级（IgM）和次级（IgG 1，IgG 2a）体液和细胞（辅助T细胞1， T辅助细胞2和CTL）在不同的小鼠中对Abeta 42的免疫应答 单倍型，包括APP/Tg F1动物;（ii）分析 高应答者和低应答者的体液和细胞免疫应答，以及 在APP/Tg小鼠中，使用多种疫苗方法（肽、DNA、噬菌体）， 展示肽，或这些免疫原的组合）;（iii） 调查年龄对最佳疫苗接种免疫应答的影响 （iv）测试这种免疫对APP/Tg小鼠的功效， APP/Tg小鼠的行为障碍并分析阿尔茨海默病样 这些动物的病理。因此，预防和治疗 将进行疫苗接种试验。

DESCRIPTION (provided by applicant): The development of APP transgenic (APP/Tg) mouse models of Alzheimer's disease (AD) provides a valuable experimental system in which to test hypotheses on the mechanisms underlying the onset and progression of AD, as well as potential therapeutic approaches. Initial reports by Schenk et al., together with recent publications, have demonstrated that immunization of APP/Tg mice with fibrillar Abeta1-42 (Abeta42)peptide blocked the deposition and initiated the removal of existing Abeta deposits from the brain. In addition, it was established that anti-Abeta antibodies could protect mice from Alzheimer's disease-like memory loss. However, a number of questions remain unanswered regarding the role of cellular immune responses to Abeta, Abeta clearance mechanisms, the potential for an autoimmune response, and problems relating to the expected variability of immune responses resulting from the highly polymorphic nature of the MHC. The cost, safety and efficacy of immunization with Abeta peptide are all critical factors that must be carefully evaluated in order to develop a successful vaccine. The ideal Abeta vaccine should target the immune response to immunogenic epitopes of Abeta that are critical for clearance, and not "non-functional" antibodies that may contribute to unwanted side effects. Thus, the goals of the current proposal are: (i) to examine extensively the primary (IgM) and secondary (IgGl, IgG2a) humoral and cellular (T-helper 1, T-helper 2, and CTL) immune responses to Abeta42 in mice of different haplotypes, including APP/Tg F1 animals; (ii) to analyze the magnitude of humoral and cellular immune responses in high and low responders, as well as in APP/Tg mice, using multiple vaccine approaches (peptides, DNA, phage displaying peptide, or a combination of these immunogens); (iii) to investigate the affect of aging on the immune response to the best vaccination regimen in APP/Tg mice; (iv) to test the efficacy of this immunization on behavioral impairment of APP/Tg mice and analyze Alzheimer's disease-like pathology in these animals. Therefore, both prophylactic and therapeutic vaccination will be tested.