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，也是许多治疗药物的靶点 目前正在开发中。在这项资助的最初几年，我们发现， 淀粉样蛋白生成AB肽在淀粉样蛋白沉积的小鼠模型中显著有效。后续 针对AJ3肽的主动免疫的人类临床试验由于在一个研究中的不良事件而暂停。 患者的子集。然而，在至少一组患者中，个体产生抗体， 大脑斑块的患者认知能力稳定。疫苗的替代品，被动免疫 具有剂量可控的优点，如果出现不良反应， 变得明显。此外，T细胞的参与，被认为是不良事件的基础， 暂停临床试验，不应采用过继转移抗体的方法。初步数据 本文报道了老年转基因小鼠的被动免疫治疗显示出显著的认知逆转， 弥散性和纤维性斑块的缺陷和显著减少。然而， 血管淀粉样沉积物和少数含有血管外血红蛋白的部位。这种相互竞争的延续 将寻求被动免疫条件，最大限度地提高认知效益和减少 实质淀粉样蛋白负荷，同时最大限度地减少潜在的有害血管损伤或其他不良反应。 后果该应用程序将测试被动免疫疗法在3个目标。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。第二个目标将比较 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 目的3，将通过检查具有优势血管的小鼠来研究替代机制。 沉积物，皮质类固醇抑制小胶质细胞活化的作用和抗体的使用， 严格的边缘分布。这些目标的成功将确定被动免疫的条件 最大限度地提高认知效益，同时保持高水平的患者安全性， 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 immunotherapyagainst the amyloidogenic ABpeptide, was remarkably effective in mouse models of amyloid deposition. Subsequent human clinical trials of active immunizationagainst the AJ3 peptide were suspended due to adverse events in a subset of patients. However, in at least one cohort of patients, individualsdeveloping 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 immunotherapyif 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 maximizethe cognitive benefits and reductions in parenchymal amyloid load while minimizingthe potentially deleterious vascular damage or other adverse consequences. This application will test passive immunotherapyin 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 passiveimmunization which maximizethe cognitive benefitswhile retaining high levels of patient safety for clinical trials in patients with Alzheimer's disease.