Development of therapeutic strategy for Alzheimer's disease by targeting amyloid precursor protein C99

淀粉样蛋白-b（Ab）在脑中的积累是阿尔茨海默病（AD）发病机制的基础。Ab通过B-和g-分泌酶介导的Ab前体蛋白（APP）的顺序蛋白水解产生。虽然G-分泌酶是治疗干预的主要靶标，但由于Notch信号传导的阻断，其活性的非选择性抑制引起严重的不良反应。我们已经确定了一个名为ILEI的分泌蛋白作为抗体生产的负调节因子。ILEI通过与g-分泌酶复合物结合并干扰其分子伴侣特性，使b-分泌酶切割的APP C-末端片段APP-C99不稳定。Notch信号传导和G-分泌酶活性不受ILEI的影响。我们还显示了ILEI的神经元表达及其在AD患者脑中的减少。ILEI的转基因过表达显著降低了AD模型小鼠的脑Ab负荷并改善了记忆缺陷。ILEI可能是开发疾病修饰疗法的合理靶点。

Accumulation of amyloid-b (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b- and g-secretase-mediated sequential proteolysis of Ab precursor protein (APP). Although g-secretase is a major target of therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling. We have identified a secretory protein named ILEI as a negative regulator of Ab production. ILEI destabilized the b-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signaling and g-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its reduction in the brains of AD patients. transgenic over expression of ILEI significantly reduced the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.