Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.
Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.
复制标题
阿尔茨海默氏症治疗抗N端Abeta 4-X和焦谷氨酸ABETA 3-X的抗体。
DOI：
10.1038/srep17338
复制
发表时间：
2015-12-02
影响因子：
4.6
通讯作者：
Bayer TA
中科院分区：
文献类型：
--
作者：
Antonios G;Borgers H;Richard BC;Brauß A;Meißner J;Weggen S;Pena V;Pillot T;Davies SL;Bakrania P;Matthews D;Brownlees J;Bouter Y;Bayer TA
全长a - β1-42和a - β1-40， n -截断焦谷氨酸a - β3-42和a - β4-42是阿尔茨海默病脑中的主要变异。a β4-42尚未被认为是一种治疗靶点。我们发现抗体NT4X及其Fab片段与Aβ4-x的游离n端和焦谷氨酸Aβ3-X反应，减轻了表达Aβ4-42的Tg4-42小鼠的神经元丢失，并完全恢复了被动免疫后的空间参考记忆缺陷。NT4X及其Fab片段还能改善a - β4-42脑室注射引起的野生型小鼠的工作记忆缺陷。NT4X降低5XFAD小鼠被动免疫后焦谷氨酸Aβ3-x、Aβx-40和硫黄素s阳性斑块负荷。Aβ1-x和Aβx-42斑块沉积不变。重要的是，我们首次证明了使用抗体NT4X的被动免疫在阿尔茨海默病小鼠模型中具有治疗益处，这表明除了焦谷氨酸a β3-x外，从第4位开始的n -截断的a β是对抗阿尔茨海默病的相关靶点。
Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain. Aβ4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aβ4-x and pyroglutamate Aβ3-X mitigated neuron loss in Tg4-42 mice expressing Aβ4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Aβ4-42. NT4X reduced pyroglutamate Aβ3-x, Aβx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aβ1-x and Aβx-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aβ starting with position four in addition to pyroglutamate Aβ3-x is a relevant target to fight Alzheimer’s disease.