Neutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific
Neutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific
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DOI：
10.1523/jneurosci.1676-11.2012
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发表时间：
2012-02-22
影响因子：
5.3
通讯作者：
Kinney, Gene G.
中科院分区：
文献类型：
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作者：
Zago, Wagner;Buttini, Manuel;Kinney, Gene G.
几种抗淀粉样β蛋白(Aβ)抗体正在评估中，用于治疗阿尔茨海默病(AD)。使用N末端导向的抗Aβ抗体bapineuzumab的临床研究表明，治疗后的AD患者脑部PET-Pittsburg-B信号减少，表明Aβ斑块减少，脑脊液中总tau蛋白和磷酸化tau蛋白水平降低。使用3D6(小鼠形式的bapineuzumab)的临床前研究表明，在转基因APP小鼠模型中，Aβ斑块和血管负担、神经性营养不良和突触密度保持不变。相比之下，很少有研究评估这种抗体与突触毒素可溶性Aβ物种的直接相互作用。在目前的报告中，我们证明了3D6与可溶性的、突触毒性的Aβ(1-42)组件结合，并阻止大鼠海马神经元的多种下游功能后果，包括改变谷氨酸AMPA受体的运输，AD型tau的磷酸化，以及树突棘的丢失。在体内，我们进一步证明了3D6可以防止突触丢失，并在AD转基因小鼠模型中急性逆转上下文恐惧条件反射任务中的行为缺陷，这两个端点被认为与突触毒素可溶性Aβ部分有关。重要的是，C端抗Aβ抗体对这些终点无效。这些研究结果表明，N端抗Aβ抗体能有效地与可溶性和不溶性的Aβ相互作用，因此特别适合于检验AD的Aβ假说。
Several anti-amyloid beta (A beta) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-A beta antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of A beta plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of A beta plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble A beta species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of A beta(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble A beta moieties. Importantly C-terminal anti-A beta antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-A beta antibodies effectively interact with both soluble and insoluble forms of A beta and therefore appear particularly well suited for testing the A beta hypothesis of AD.