Cohen A D, Ikonomovic M D, Abrahamson E E, Paljug W R, Dekosky S T, Lefterov I M, Koldamova R P, Shao L, Debnath M L, Mason N S, Mathis C A, Klunk W E
University of Pittsburgh, Room 1422 WPIC, 3811 O'Hara Street, Pittsburgh, PA 15213-2593, USA.
Lett Drug Des Discov. 2009 Sep;6(6):437. doi: 10.2174/157018009789057526.
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.
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，其基于这样的假说，即大脑中β淀粉样蛋白（Aβ）沉积物的增加是AD的主要病因。几个研究小组专注于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在体外可抑制Aβ聚集并防止Aβ神经毒性。这里描述的药物均为刚果红的小分子Aβ结合剂（SMAβBA）衍生物。
在此，我们研究了这些SMAβBA对人早老素-1（PS1）和APP基因突变导致早发性AD的双转基因小鼠的抗淀粉样蛋白特性。小鼠分别用甲氧基-X04、X:EE:B34和X:034-3-OMe1进行治疗。治疗后，使用组织化学检查大脑中的Aβ沉积，并使用酶联免疫吸附测定法测定可溶性和不溶性Aβ水平。
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治疗的PS1/APP小鼠显示总Aβ负荷降低、Aβ纤维负荷降低以及平均斑块大小减小。用甲氧基-X04治疗还导致不溶性Aβ水平降低。结构相似的化合物X:034:3-OMe1对这些指标均无显著影响。SMAβBA的有效性可能与对Aβ的结合亲和力和进入大脑的能力有关，但其他因素似乎也起作用。
这些数据表明，SMAβBA可能在AD发病机制期间显著降低大脑中的淀粉样蛋白负荷，并且单独或与免疫疗法联合使用可能是有用的治疗方法。
