Netzer William J, Bettayeb Karima, Sinha Subhash C, Flajolet Marc, Greengard Paul, Bustos Victor
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1389-1394. doi: 10.1073/pnas.1620963114. Epub 2017 Jan 23.
Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.
神经毒性淀粉样β肽（Aβ）是阿尔茨海默病（AD）的主要驱动因素，由淀粉样前体蛋白（APP）依次经β-分泌酶（BACE）和γ-分泌酶切割形成。我们之前的研究表明，抗癌药物格列卫通过间接抑制γ-分泌酶活性来降低Aβ水平。在此我们报告，格列卫还通过另一种细胞机制实现其降低Aβ的作用。它使APP对BACE介导的蛋白水解更不易感，而不抑制BACE的酶活性或其他BACE底物的加工。这种效应与APP A673T的表型非常相似，A673T是最近发现的一种突变，可保护携带者免受AD和年龄相关认知衰退的影响。此外，格列卫诱导形成一组特定的APP C末端片段，在表达APP保护性突变的细胞以及暴露于传统BACE抑制剂的细胞中也观察到这种片段。这些格列卫的表型需要细胞内酸性pH，并且与酪氨酸激酶抑制无关，因为一种缺乏酪氨酸激酶抑制活性的相关化合物DV2-103对APP代谢也有类似作用。此外，DV2-103在啮齿动物脑中高浓度蓄积，在那里它能迅速降低Aβ水平。这项研究表明，长期使用间接调节APP的BACE加工但不影响其他BACE底物且能在脑中达到治疗浓度的药物，可能对预防或延缓AD的发病有效，并且可能比非选择性BACE抑制剂药物更安全。
