Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain.
Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain.
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DOI：
10.1371/journal.pone.0040027
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bredesen DE
中科院分区：
文献类型：
--
作者：
Libeu CA;Descamps O;Zhang Q;John V;Bredesen DE
与阿尔茨海默病相关的事件之一是淀粉样前体蛋白（APP）的α-裂解与β-裂解的失调。α-裂解产物（sAPPα）具有神经保护特性，而β-裂解产物Aβ1-42肽具有神经毒性。已显示APP的二聚化影响APP的α-和β-裂解的相对速率。因此，发现干扰APP胞外域的二聚化并增加APP的α-裂解的化合物可能导致开发阿尔茨海默病的新疗法。APP胞外结构域片段通过E2和Aβ同源结构域二聚化，检测其内源荧光发现，在Aβ寡聚体（与胞外结构域二聚体结合）和Aβ片段（使胞外结构域二聚体不稳定）结合后，片段荧光发生显著变化。扩展该技术以显示含RERMS的肽（APP 695 328-332）、双硫仑和硫仑也抑制胞外域片段的二聚化。该活性用小角X射线散射证实。AlphaLISA试验中双硫仑和硫仑的活性分析表明，两种化合物均显著增强7 W-CHO和B103神经母细胞瘤细胞产生sAPPα。这些观察结果表明，存在一类调节APP胞外域的构象并影响APP的α-与β-裂解的比率的化合物。这些化合物为开发一类新的阿尔茨海默病治疗剂提供了理论基础。
One of the events associated with Alzheimer's disease is the dysregulation of α- versus β-cleavage of the amyloid precursor protein (APP). The product of α-cleavage (sAPPα) has neuroprotective properties, while Aβ1-42 peptide, a product of β-cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of α- and β- cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the α-cleavage of APP could lead to the development of new therapies for Alzheimer's disease. Examining the intrinsic fluorescence of a fragment of the ectodomain of APP, which dimerizes through the E2 and Aβ-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of Aβ oligomers—which bind to dimers of the ectodomain— and Aβ fragments—which destabilize dimers of the ectodomain. This technique was extended to show that RERMS-containing peptides (APP695 328–332), disulfiram, and sulfiram also inhibit dimerization of the ectodomain fragment. This activity was confirmed with small angle x-ray scattering. Analysis of the activity of disulfiram and sulfiram in an AlphaLISA assay indicated that both compounds significantly enhance the production of sAPPα by 7W-CHO and B103 neuroblastoma cells. These observations demonstrate that there is a class of compounds that modulates the conformation of the APP ectodomain and influences the ratio of α- to β-cleavage of APP. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease.
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