Multiple Approaches to ABeta Vaccination in Animal Mode*

描述(申请人提供)：转基因APP的开发 (APP/TG)小鼠阿尔茨海默病(AD)模型提供了有价值的 一种实验系统，用来检验关于潜在机制的假设 阿尔茨海默病的发生和发展，以及潜在的治疗方法。 Schenk等人的初步报告与最近的出版物一起， Abeta1-42纤维蛋白免疫APP/TG小鼠的实验研究 (Abeta42)肽阻断沉积并启动对现有物质的清除 Aβ从大脑中沉积下来。此外，已确定抗Abeta抗体 抗体可以保护小鼠免受类似阿尔茨海默病的记忆丧失。 然而，一些问题仍然没有得到回答，关于 对Abeta的细胞免疫反应，Abeta清除机制，潜在的 对于自身免疫反应，以及与预期变异性相关的问题 由MHC的高度多态性质引起的免疫反应。 Abeta多肽免疫的成本、安全性和有效性都是 必须仔细评估的关键因素，以便制定 成功的疫苗。理想的Abeta疫苗应该针对免疫反应 对清除至关重要的免疫原性Abeta表位，而不是 可能会导致不良副作用的“非功能性”抗体。 因此，本提案的目标是：(1)广泛审查 初级(IgM)和次级(IgG1、IgG2a)体液和细胞(T辅助细胞1， T辅助细胞2和CTL)对Abeta42的免疫应答 单倍型，包括APP/TG F1动物；(Ii)分析 高、低应答者的体液和细胞免疫反应以及 在APP/TG小鼠中，使用多种疫苗方法(多肽、DNA、噬菌体 展示多肽或这些免疫原的组合)； 探讨衰老对最佳疫苗免疫应答的影响 APP/TG小鼠的免疫方案；(Iv)测试该免疫方案对小鼠的效果 APP/TG小鼠行为损害及类阿尔茨海默病分析 这些动物的病理学。因此，无论是预防还是治疗 将对疫苗接种进行测试。

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.