The conformational epitope for a new Aβ42 protofibril-selective antibody partially overlaps with the peptide N-terminal region.
The conformational epitope for a new Aβ42 protofibril-selective antibody partially overlaps with the peptide N-terminal region.
复制标题
新的Aβ42原纤维选择性抗体的构象表位部分与肽N末端区域重叠。
DOI：
10.1111/jnc.14211
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发表时间：
2017-12
影响因子：
4.7
通讯作者：
Nichols MR
中科院分区：
文献类型：
--
作者：
Colvin BA;Rogers VA;Kulas JA;Ridgway EA;Amtashar FS;Combs CK;Nichols MR
淀粉样蛋白-β肽（a β）的聚集和积累是阿尔茨海默病（AD）的关键组成部分。虽然单体a β似乎是良性的，但低聚物采用了一种有害的生物结构。这些可溶性结构可以通过对聚集的Aβ具有选择性的抗体在AD脑组织中检测到。原原纤维是可溶性a β低聚物的一个子集，被描述为小的（<100 nm）曲线组装，富含β-片结构。我们自己的体外研究表明，与Aβ42单体或不溶性Aβ42原纤维相比，小胶质细胞对可溶性Aβ42原纤维更敏感。原原纤维与小胶质细胞相互作用，触发toll样受体信号，引发细胞因子转录和表达，并迅速被细胞吸收。由于这种Aβ物种的重要性，我们试图开发一种选择性识别原纤维的抗体，而不是其他Aβ物种。用分离的a β42原原纤维免疫家兔，可产生对a β42原原纤维具有强亲和力的高效价血清。该抗血清（AbSL）对Aβ42原纤维的选择性优于Aβ42单体和Aβ42原纤维。AbSL在AD转基因小鼠脑切片中不与淀粉样蛋白前体蛋白发生反应，并表现出明显的病理特征。与靶向残基1-16的Aβ抗体的竞争研究表明，AbSL的构象表位以某种方式涉及原原纤维的n端区域。新开发的抗体可能在AD组织和患者中具有潜在的诊断和治疗用途，并且针对AD的原纤维可能具有有益的作用。原原纤维是可溶性低聚淀粉样蛋白-β (a β)的一个亚群，它与小胶质细胞相互作用，触发toll样受体信号，引发细胞因子转录和表达，并迅速被细胞吸收。由于这种Aβ物种的重要性，我们试图开发一种选择性识别原纤维的抗体，而不是其他Aβ物种。用分离的a β42原原纤维免疫家兔，可产生对a β42原原纤维具有强亲和力的高效价血清。图片显示了一只15个月大的APP/PS1小鼠的脑切片中a β积累的区域。用Aβ42原纤维选择性AbSL抗血清（绿色）和4G8单克隆抗体（红色）对脑组织样本进行免疫染色，4G8单克隆抗体对聚集和未聚集的Aβ残基17-24有反应。在合并后的图像中可以看到很少的共定位（黄色）。每个抗体的反应和定位都有显著差异，这表明abl可以独特地访问Aβ病理区域。人们希望构象选择性Aβ抗体的发展将有助于阿尔茨海默病的研究、诊断和潜在的治疗。淀粉样蛋白-β肽（a β）的聚集和积累是阿尔茨海默病（AD）的关键组成部分。聚集过程产生各种可溶（原纤维）和不可溶（原纤维）物种。由于原原纤维的重要性，一种被称为AbSL的抗血清被开发出来，并被发现对Aβ原原纤维比单体和原纤维有选择性。这种新开发的抗体可能有潜在的诊断和治疗用途。
Aggregation and accumulation of amyloid-β peptide (Aβ) is a key component of Alzheimer's disease (AD). While monomeric Aβ appears to be benign, oligomers adopt a biologically detrimental structure. These soluble structures can be detected in AD brain tissue by antibodies that demonstrate selectivity for aggregated Aβ. Protofibrils are a subset of soluble oligomeric Aβ species and are described as small (<100 nm) curvilinear assemblies enriched in β-sheet structure. Our own in vitro studies demonstrate that microglial cells are much more sensitive to soluble Aβ42 protofibrils compared to Aβ42 monomer or insoluble Aβ42 fibrils. Protofibrils interact with microglia, trigger Toll-like receptor signaling, elicit cytokine transcription and expression, and are rapidly taken up by the cells. Due to the importance of this Aβ species, we sought to develop an antibody that selectively recognizes protofibrils over other Aβ species. Immunization of rabbits with isolated Aβ42 protofibrils generated a high-titer serum with a strong affinity for Aβ42 protofibrils. The anti-serum, termed AbSL, was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL did not react with amyloid precursor protein and recognized distinct pathological features in AD transgenic mouse brain slices. Competition studies with an Aβ antibody that targets residues 1-16 indicated that the conformational epitope for AbSL involved the N-terminal region of protofibrils in some manner. The newly-developed antibody may have potential diagnostic and therapeutic uses in AD tissue and patients, and targeting of protofibrils in AD may have beneficial effects. Protofibrils are a subset of soluble oligomeric amyloid-β (Aβ) species, which interact with microglia, trigger Toll-like receptor signaling, elicit cytokine transcription and expression, and are rapidly taken up by the cells. Due to the importance of this Aβ species, we sought to develop an antibody that selectively recognizes protofibrils over other Aβ species. Immunization of rabbits with isolated Aβ42 protofibrils generated a high-titer serum with a strong affinity for Aβ42 protofibrils. The image shows an area of Aβ accumulation in a brain slice from a 15 month old APP/PS1 mouse. The brain tissue sample was immunostained with Aβ42 protofibril-selective AbSL antiserum (green) and 4G8 monoclonal antibody (red), which is reactive to residues 17-24 of aggregated and unaggregated Aβ. Very little colocalization (yellow) can be seen in this merged image. Notable differences were observed in the response and localization of each antibody indicating areas of Aβ pathology that are uniquely accessible by AbSL. It is hoped that development of conformationally-selective Aβ antibodies will aid in Alzheimer's disease research, diagnostics, and potentially therapeutics. Aggregation and accumulation of amyloid-β peptide (Aβ) is a key component of Alzheimer's disease (AD). The aggregation process yields a variety of soluble (protofibrils) and insoluble (fibrils) species. Due to the importance of protofibrils, an anti-serum, termed AbSL, was developed and found to be selective for Aβ protofibrils over monomers and fibrils. The newly-developed antibody may have potential diagnostic and therapeutic uses.
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影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
针对适当的淀粉样β神经元毒素：阿尔茨海默病免疫治疗的前进之路。
DOI：
10.1186/alzrt272
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Goure WF;Krafft GA;Jerecic J;Hefti F
通讯作者：
Hefti F
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
4.7
作者：
Lambert, MP;Viola, KL;Klein, WL
通讯作者：
Klein, WL
影响因子：
5.3
作者：
Deshpande, Atul;Kawai, Hideki;Busciglio, Jorge
通讯作者：
Busciglio, Jorge