Treatment with scFv-h3D6 Prevented Neuronal Loss and Improved Spatial Memory in Young 3xTg-AD Mice by Reducing the Intracellular Amyloid-β Burden
Treatment with scFv-h3D6 Prevented Neuronal Loss and Improved Spatial Memory in Young 3xTg-AD Mice by Reducing the Intracellular Amyloid-β Burden
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DOI：
10.3233/jad-190484
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Villegas, Sandra
中科院分区：
文献类型：
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作者：
Esquerda-Canalsa, Gisela;Roda, Alejandro R.;Villegas, Sandra
在阿尔茨海默病（AD）患者和动物模型的大脑中已经描述了淀粉样蛋白- β (A β)肽的细胞内沉积。最近在一个三重转基因AD （3xTg-AD）小鼠模型中报道了细胞内淀粉样蛋白负荷与神经退行性变之间的相关性。在本研究中，我们评估了scFv- h3d6（一种源自抗体bapineuzumab的抗A β单链可变片段（scFv））对5月龄3xTg-AD雌性小鼠淀粉样蛋白病理的影响，重点关注细胞内A β清除、神经元存活和功能能力。我们还检查了神经炎症和周围器官样本的组织学，以检测任何不良反应。单次腹腔注射scFv-h3D6可显著降低大鼠大脑皮层深层、海马锥体细胞层和杏仁核基底外侧的细胞内A β负荷。治疗可以防止海马和杏仁核的神经元丢失，而星形胶质细胞增生和小胶质细胞增生均未引起。相反，治疗后白髓大小的增加表明脾脏可能参与了清除机制。虽然这种治疗并没有改善痴呆样症状的行为和心理症状，但认知测试的结果表明，空间记忆有了明显的改善。这些发现表明，scFv-h3D6治疗作用的机制是清除细胞内A β，随后预防神经元丢失和改善认知障碍。在神经炎症和肝肾功能方面，治疗是安全的，但对脾有一些影响。
The intracellular deposition of amyloid-beta (A beta) peptides has been described in the brains of both Alzheimer's disease (AD) patients and animal models. A correlation between the intracellular amyloid burden and neurodegeneration has recently been reported in a triple-transgenic AD (3xTg-AD) murine model. In the present study, we assessed the effect of scFv-h3D6, an anti-A beta single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular A beta clearance, neuronal survival, and functional abilities. We also examined neuroinflammation and the histology of peripheral organ samples to detect any adverse effects. A single intraperitoneal injection of scFv-h3D6 dramatically reduced intracellular A beta burden in the deep layers of the cerebral cortex, pyramidal cells layer of the hippocampus, and basolateral amygdalar nucleus. The treatment prevented neuronal loss in the hippocampus and amygdala, while neither astrogliosis nor microgliosis was induced. Instead, an increase in the size of the white pulp after the treatment indicated that the spleen could be involved in the clearance mechanism. Although the treatment did not ameliorate behavioral and psychological symptoms of dementia-like symptoms, the results of cognitive testing pointed to a noticeable improvement in spatial memory. These findings indicated that the mechanism underlying the therapeutic effect of scFv-h3D6 was the clearance of intracellular A beta with subsequent prevention of neuronal loss and amelioration of cognitive disabilities. The treatment was safe in terms of neuroinflammation and kidney and liver function, whereas some effects on the spleen were observed.