Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization
Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization
复制标题
DOI：
10.1096/fj.06-7993com
复制
发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Tang, Jordan
中科院分区：
文献类型：
--
作者：
Chang, Wan-Pin;Downs, Deborah;Tang, Jordan
膜蛋白酶2（β-分泌酶，BACE 1）是启动β-淀粉样蛋白前体蛋白裂解的蛋白酶，导致淀粉样蛋白-β（A β）的产生和阿尔茨海默病（AD）的发作。通过靶向memapsin 2降低A β是开发新的AD治疗的主要策略。在这里，在概念验证研究中，我们表明用memapsin 2免疫转基因AD小鼠（Tg 2576）导致A β减少和认知改善。为了研究这种疗法的基础，我们证明了抗-memapsin 2（抗-M2）抗体在培养的细胞中迅速内化并减少A β的产生。这些抗体也有效地穿过血脑屏障到达大脑。对2个月和10个月的Tg 2576小鼠进行免疫接种，并分别在10个月和6个月内进行监测。与对照组相比，我们观察到免疫小鼠的血浆和脑A β（40）和A β（42）显著降低（类似于35%）。在两个队列中，免疫小鼠也表现出比对照组更好的认知能力。脑组织学分析未发现免疫小鼠中T细胞/小胶质细胞/星形胶质细胞活化的证据，表明不存在炎症反应。这些结果表明，Tg 2576中的memapsin 2免疫在减少A β产生和改善认知功能方面是有效的，并且目前的方法值得进一步研究作为AD的治疗。
Memapsin 2 (beta-secretase, BACE1) is the protease that initiates cleavage of beta-amyloid precursor protein leading to the production of amyloid-beta (A beta) and the onset of Alzheimer's disease (AD). Reducing A beta by targeting memapsin 2 is a major strategy in developing new AD therapy. Here, in a proof-of-concept study, we show that immunization of transgenic AD mice (Tg2576) with memapsin 2 resulted in A beta reduction and cognitive improvement. To study the basis of this therapy, we demonstrated that anti-memapsin 2 (anti-M2) antibodies were rapidly internalized and reduced A beta production in cultured cells. These antibodies also effectively crossed the blood-brain barrier to reach the brain. Two-and 10-month Tg2576 mice were immunized and monitored over 10 and 6 months, respectively. We observed a significant decrease of plasma and brain A beta(40) and A beta(42) (similar to 35%) in the immunized mice as compared to controls. Immunized mice also showed better cognitive performance than controls in both cohorts. Brain histological analyses found no evidence of T cell/microglia/astrocyte activation in the immunized mice, suggesting the absence of inflammatory responses. These results suggest that memapsin 2 immunization in Tg2576 was effective in reducing A beta production and improving cognitive function and that the current approach warrants further investigation as a therapy for AD.