Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice.
Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice.
复制标题
DOI：
10.1186/s40478-015-0217-z
复制
发表时间：
2015-07-04
影响因子：
7.1
通讯作者：
Thal DR
中科院分区：
文献类型：
--
作者：
Balakrishnan K;Rijal Upadhaya A;Steinmetz J;Reichwald J;Abramowski D;Fändrich M;Kumar S;Yamaguchi H;Walter J;Staufenbiel M;Thal DR
淀粉样β蛋白（Aβ）在脑中的沉积是阿尔茨海默病（AD）的标志。通过Aβ抗体治疗清除Aβ已被开发为一种潜在的AD治疗策略。第一次临床试验表明，既没有停止也没有减少疾病的进展。最近，我们发现人脑中可溶性和不溶性Aβ聚集体的形成遵循三个生化成熟阶段（B-Aβ阶段）的分级序列。为了测试B-Aβ阶段对Aβ免疫治疗的影响，我们处理了表达携带瑞典突变的人淀粉样前体蛋白（APP）的转基因小鼠，（KM670/671NL; APP 23）与Aβ-抗体β1或磷酸盐缓冲盐水（PBS），1）在3个月时，树突变性和斑块沉积开始前，和2）在7个月时，在Aβ斑块沉积和树突变性开始后。在5月龄时，APP 23脑中的第一个Aβ聚集体由未修饰的Aβ（代表B-Aβ 1期）组成，而在11月龄时，在β1和PBS处理的动物中均发现含有N末端截短、焦谷氨酸修饰的Aβ N3 pE和磷酸化Aβ（代表B-Aβ 3期）的成熟Aβ聚集体。仅在5个月时处死的3个月龄β1处理动物中观察到对连合神经元具有高度分枝树突树的保护作用。当在7月龄开始给药时，在11月龄处死的β1和PBS给药的APP 23小鼠之间未观察到健康连合神经元数量的差异。只要Aβ聚集体不存在或代表B-Aβ 1期，Aβ抗体处理就能够保护神经元免于树突状变性，但在成熟Aβ聚集体的后期（B-Aβ 3期）没有保护或治疗作用。这些数据表明，Aβ聚集体的成熟阶段对APP 23小鼠的潜在治疗效果有影响。本文的在线版本（doi：10.1186/s40478-015-0217-z）包含补充材料，可供授权用户使用。
The deposition of the amyloid β protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aβ by Aβ-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages). To test the impact of the B-Aβ stage on Aβ immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aβ-antibody β1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aβ plaque deposition and dendrite degeneration. At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ (representing B-Aβ stage 1) whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified AβN3pE and phosphorylated Aβ (representing B-Aβ stage 3) were found at 11 months of age in both β1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between β1- and PBS-treated APP23 mice sacrificed with 11 months. Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3). These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice. The online version of this article (doi:10.1186/s40478-015-0217-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
15.1
作者：
Garcia-Alloza M;Subramanian M;Thyssen D;Borrelli LA;Fauq A;Das P;Golde TE;Hyman BT;Bacskai BJ
通讯作者：
Bacskai BJ
影响因子：
2.5
作者：
Akiyama, H;Schwab, C;McGeer, PL
通讯作者：
McGeer, PL
影响因子：
14.5
作者：
Capetillo-Zarate, Estibaliz;Staufenbiel, Matthias;Thal, Dietmar Rudolf
通讯作者：
Thal, Dietmar Rudolf
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
DOI：
10.1073/pnas.0703793104
发表时间：
2007-12-04
影响因子：
11.1
作者：
Habicht, Gernot;Haupt, Christian;Faendrich, Marcus
通讯作者：
Faendrich, Marcus