A Natural Squamosamide Derivative FLZ Reduces Amyloid-β Production by Increasing Non-Amyloidogenic AβPP Processing
A Natural Squamosamide Derivative FLZ Reduces Amyloid-β Production by Increasing Non-Amyloidogenic AβPP Processing
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DOI：
10.3233/jad-2009-1133
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Luo, Yuan
中科院分区：
文献类型：
--
作者：
Hou, Yan;Yu, Young-Beob;Luo, Yuan
大量证据支持A β在阿尔茨海默病（AD）发病机制中的核心作用。我们已经证明，FLZ，天然squamosamide的合成环状类似物，在细胞和小鼠模型中表现出神经保护作用，这表明FLZ作为治疗AD的候选化合物的未来研究。在这项研究中，我们发现在表达淀粉样β蛋白（A β）的神经母细胞瘤细胞中，FLZ减少了A β的产生，并且与培养基中淀粉样β蛋白前体（sA β PP α）的可溶性α-分泌酶衍生片段的增加相关。此外，ADAM 10和A β PP的活性形式在FLZ处理的细胞的细胞表面升高，与ADAM 10和A β PP在膜上的增强的共定位一致。用蛋白运输抑制剂布雷菲德菌素预处理，阻断FLZ诱导的ADAM 10向细胞表面的易位和sA β PP α向培养基的释放。此外，口服FLZ的APPswe/PS1转基因小鼠显著降低A β的水平，与激活的ADAM 10，在海马。计算机模拟预测表明FLZ的结构与吸收和渗透性的药物样规则相容。这些发现表明FLZ通过促进A β PP非淀粉样蛋白生成α分泌酶加工来减少A β产生。因此，FLZ可能具有治疗AD的治疗潜力。
Substantial evidence supports a central role of A beta in the pathogenesis of Alzheimer's disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that the production of amyloid-beta (A beta) was reduced by FLZ in A beta-expressing neuroblastoma cells, and correlated with an increase in the soluble alpha-secretase derived fragment of the amyloid-beta protein precursor (sA beta PP alpha) in the medium. Moreover, the active form of ADAM10 and A beta PP were elevated at the cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and A beta PP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sA beta PP alpha to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of A beta, paralleling with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ is compatible with the drug-like rules for absorption and permeability. These findings suggest that FLZ reduces A beta production by promoting A beta PP non-amyloidogenic alpha-secretase processing. As such, FLZ may have therapeutic potential for the treatment of AD.