Functional Consequences of Vaccination in AD Tg Mice

淀粉样蛋白是阿尔茨海默病的主要病理特征，也是目前正在开发的许多治疗剂的靶点。在该基金的最初几年，我们发现针对淀粉样蛋白生成的Abeta肽的免疫疗法在淀粉样蛋白沉积的小鼠模型中非常有效。随后针对AJ3肽的主动免疫的人类临床试验由于患者子集中的不良事件而暂停。然而，在至少一组患者中，产生与脑斑块反应的抗体的个体受益于认知稳定。疫苗的替代品，被动免疫 具有控制剂量的优点，并且如果不良反应变得明显则能够终止免疫治疗。此外，被认为是暂停的临床试验中不良事件的基础的T细胞参与不应存在于抗体的过继转移方法中。本文报道的老年转基因小鼠被动免疫治疗的初步数据显示，认知缺陷显著逆转，弥漫性和纤维性斑块显著减少。然而，血管淀粉样蛋白沉积物和少数含有血管外血红蛋白的部位也有增加。这种竞争性的继续将寻求被动免疫条件，其使认知益处和实质淀粉样蛋白负荷的减少最大化，同时使潜在有害的血管损伤或其他不利的免疫反应最小化。 后果该应用程序将在3个目标中测试被动免疫疗法。第一个目标将评估年龄、淀粉样蛋白负荷和淀粉样蛋白去除速度对这些过程的影响。第二个目的是比较具有不同表位特异性的抗体并测量不同抗体片段的功效。在目标3中，将通过检查血管沉积占优势的小鼠、皮质类固醇抑制小胶质细胞活化的作用以及使用具有严格外周分布的抗体来研究替代机制。这些目标的成功将确定被动免疫的条件，使认知益处最大化，同时保持高水平的患者安全性，用于临床试验， 老年痴呆症患者

Amyloid is a major pathological feature of Alzheimer's disease and a target of many therapeutic agents currently under development. In the first years of this grant we found that immunotherapy against the amyloidogenic Abeta peptide, was remarkably effective in mouse models of amyloid deposition. Subsequent human clinical trials of active immunization against the AJ3 peptide were suspended due to adverse events in a subset of patients. However, in at least one cohort of patients, individuals developing antibodies which react with brain plaques benefited with cognitive stabilization. An alternative to vaccines, passive immunization has the advantages of controlled dosing and the ability to terminate immunotherapy if adverse reactions become manifest. Moreover, T-cell involvement, argued to be the basis for the adverse events in the suspended clinical trial, should not be present with adoptive transfer of antibody approaches. Preliminary data reported here with passive immunotherapy of old transgenic mice shows remarkable reversal of cognitive deficits and dramatic reductions in diffuse and fibrillar plaques. However, there were also increases in vascular amyloid deposits and a few sites containing extravascular hemoglobin. This competing continuation will seek passive immunization conditions which maximize the cognitive benefits and reductions in parenchymal amyloid load while minimizing the potentially deleterious vascular damage or other adverse consequences. This application will test passive immunotherapy in 3 aims. The first aim will evaluate the effects of age, amyloid load, and speed of amyloid removal on these processes. The second aim will compare antibodies with different epitopic specificities and measure the efficacy of different antibody fragments. In aim 3, alternative mechanisms will be investigated by examining mice with a preponderance of vascular deposits, the effects of corticosteroid suppression of microglia activation and the use of antibodies with strictly peripheral distribution . Success in these aims will identify conditions of passive immunization which maximize the cognitive benefits while retaining high levels of patient safety for clinical trials in patients with Alzheimer's disease.