AIMS: One promising approach for treatment of Alzheimer's disease (AD) is use of anti-amyloid therapies, based on the hypothesis that increases in amyloid-beta (Aβ) deposits in brain are a major cause of AD. Several groups have focused on Aβ immunotherapy with some success. Small molecules derivatives of Congo red have been shown to inhibit Aβ aggregation and protect against Aβ neurotoxicity in vitro. The agents described here are all small molecule Aβ-binding agents (SMAβBA's) derivatives of Congo red. MAIN METHODS: Here, we have explored the anti-amyloid properties of these SMAβBA's in mice doubly transgenic for human prensenilin-1 (PS1) and APP gene mutations that cause early-onset AD. Mice were treated with either methoxy-X04, X:EE:B34 and X:034-3-OMe1. After treatment, brains were examined for Aβ-deposition, using histochemistry, and soluble and insoluble Aβ levels were determined using ELISA. KEY FINDINGS: A range of anti-amyloid activity was observed with these three compounds. PS1/APP mice treated with methoxy-X04 and X:EE:B34 showed decrease in total Aβ load, a decrease in Aβ fibril load, and a decrease in average plaque size. Treatment with methoxy-X04 also resulted in a decrease in insoluble Aβ levels. The structurally similar compound, X:034:3-OMe1, showed no significant effect on any of these measures. The effectiveness of the SMAβBA's may be related to a combination of binding affinity for Aβ and entry into brain, but other factors appear to apply as well. SIGNIFICANCE: These data suggest that SMAβBA's may significantly decrease amyloid burden in brain during the pathogenesis of AD and could be useful therapeutics alone, or in combination with immunotherapy.

中文翻译：

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小分子 Aβ 结合剂在 PS1/APP 小鼠中的抗淀粉样蛋白作用

目的：治疗阿尔茨海默病 (AD) 的一种有前景的方法是使用抗淀粉样蛋白疗法，基于大脑中淀粉样蛋白 β (Aβ) 沉积物增加是 AD 的主要原因这一假设。几个小组专注于 Aβ 免疫疗法并取得了一些成功。刚果红的小分子衍生物已被证明可抑制 Aβ 聚集并在体外防止 Aβ 神经毒性。这里描述的试剂都是刚果红的小分子 Aβ 结合剂 (SMAβBA) 衍生物。主要方法：在这里，我们已经探索了这些 SMAβBA 在双转基因小鼠中的抗淀粉样蛋白特性，这些小鼠是导致早发性 AD 的人早老素-1 (PS1) 和 APP 基因突变。小鼠用甲氧基-X04、X:EE:B34 和 X:034-3-OMe1 处理。治疗后，使用组织化学检查大脑的 Aβ 沉积，使用ELISA测定可溶性和不溶性Aβ水平。主要发现： 观察到这三种化合物具有一系列抗淀粉样蛋白活性。用甲氧基-X04 和 X:EE:B34 处理的 PS1/APP 小鼠显示总 Aβ 负荷减少，Aβ 原纤维负荷减少，平均斑块大小减小。用甲氧基-X04 处理也导致不溶性 Aβ 水平降低。结构相似的化合物 X:034:3-OMe1 对这些测量中的任何一个都没有显着影响。SMAβBA 的有效性可能与 Aβ 的结合亲和力和进入大脑的结合有关，但其他因素似乎也适用。意义：这些数据表明，在 AD 发病过程中，SMAβBA's 可能显着降低大脑中的淀粉样蛋白负荷，并且可能单独作为有用的治疗方法，