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药物的靶点。在这笔赠款的头几年，我们发现针对产生淀粉样蛋白的Abeta肽的免疫治疗在淀粉样蛋白沉积的小鼠模型中非常有效。随后针对AJ3多肽的主动免疫的人类临床试验因部分患者的不良事件而暂停。然而，在至少一组患者中，开发出与脑斑块发生反应的抗体的个体有利于认知稳定。疫苗的另一种选择，被动免疫 具有可控剂量的优点，并能够在出现不良反应时终止免疫治疗。此外，T细胞的参与被认为是暂停的临床试验中不良事件的基础，不应该出现在抗体过继转移的方法中。这里报道的对老年转基因小鼠进行被动免疫治疗的初步数据显示，认知障碍显著逆转，弥漫性斑块和纤维斑块显著减少。然而，血管淀粉样蛋白沉积和少数含有血管外血红蛋白的部位也增加了。这种竞争的延续将寻求被动免疫条件，以最大化认知益处和减少实质淀粉样蛋白负荷，同时将潜在的有害血管损伤或其他不利因素降至最低。 后果。这项应用将在3个目标中测试被动免疫治疗。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效力。在目标3中，将通过检测血管沉积占优势的小鼠、皮质类固醇抑制小胶质细胞激活的效果以及使用严格外围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，同时保持患者在临床试验中的高水平安全性。 阿尔茨海默病患者。

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.