Vaccination of Alzheimer's model mice with Aβ derivative in alum adjuvant reduces Aβ burden without microhemorrhages
Vaccination of Alzheimer's model mice with Aβ derivative in alum adjuvant reduces Aβ burden without microhemorrhages
复制标题
DOI：
10.1111/j.1460-9568.2006.05149.x
复制
发表时间：
2006-11-01
影响因子：
3.4
通讯作者：
Sigurdsson, Einar M.
中科院分区：
文献类型：
--
作者：
Asuni, Ayodeji A.;Boutajangout, Allal;Sigurdsson, Einar M.
免疫疗法对阿尔茨海默病（AD）和其他构象障碍有很大的希望，但需要克服某些不良反应。在第一次AD疫苗接种试验中观察到的脑膜脑炎可能与由免疫原淀粉样蛋白β（A β）1-42和佐剂QS-21引起的过度细胞介导的免疫有关。为了避免这种毒性，我们一直在明矾佐剂中使用A β衍生物，以促进体液免疫。免疫治疗的其他潜在副作用是血管淀粉样蛋白和相关微血管生成增加，这可能与实质淀粉样蛋白的快速清除有关。在这里，我们确定了我们的免疫策略是否与这种形式的毒性有关，以及治疗效果是否与年龄有关。Tg 2576小鼠和野生型同窝小鼠从11个月或19个月开始免疫，并在24个月处死前评价其行为。随后，评估斑块和血管A β负荷、A β水平和相关病理学。在淀粉样变性的尖端开始的治疗使皮质A β存款负担降低31%，A β水平降低30- 37%，这与认知改善相关。相比之下，从19个月开始的治疗，当病理学已经明确时，没有免疫原性，因此没有减少A β负荷或改善认知。值得注意的是，与几项A β抗体研究相比，11-24个月治疗组中的免疫治疗降低了A β负荷，没有增加脑出血或血管A β沉积。这些发现表明，当与适用于人类的佐剂一起使用时，我们的方法年龄依赖性地改善认知并降低A β负荷，而不增加血管A β沉积或微血管化。
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (A beta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using A beta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-A beta burden, A beta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical A beta deposit burden by 31% and A beta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce A beta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced A beta burden, did not increase cerebral bleeding or vascular A beta deposits in contrast to several A beta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces A beta burden when used with an adjuvant suitable for humans, without increasing vascular A beta deposits or microhemorrhages.