Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure
Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure
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DOI：
10.1111/j.1471-4159.2010.07118.x
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发表时间：
2011-02-01
影响因子：
4.7
通讯作者：
Weggen, Sascha
中科院分区：
文献类型：
--
作者：
Hahn, Stefanie;Bruening, Tanja;Weggen, Sascha
γ-分泌酶调节剂（GSMs）抑制淀粉样蛋白A β 42肽的产生，并且是用于治疗或预防阿尔茨海默病（AD）的有希望的药剂。最近，出现了具有良好药理学特性的第二代GSM，但缺乏评估其体内疗效的临床前研究。这些研究依赖于表达与早发性家族性AD相关的淀粉样前体蛋白（APP）和早老素（PSEN）突变的转基因小鼠模型。以前，我们已经表明，某些PSEN 1突变减弱了培养细胞对GSM的反应，并可能混淆AD小鼠模型的体内研究。然而，家族性AD突变的不同组合可能具有协同或相反的作用，我们现在已经系统地确定了当前AD模型中存在的APP和PSEN 1突变的反应。使用有效的酸性GSM，我们发现APP突变，无论是单一突变还是组合突变，都不会影响GSM的效力。相比之下，所有用于加速AD模型病理变化的PSEN 1突变都强烈减弱了GSM的A β 42降低活性，但有两个例外（M146 L，A246 E）。用有效的非酸性GSM获得了类似的结果，表明PSEN 1突变的减弱作用不能简单地通过增加的效力或结构变化来克服。值得注意的是，两种非酸性化合物完全补偿了PSEN 1-G384 A突变的减弱作用。总之，我们的研究结果表明，大多数AD模型与快速病理和先进的表型是不适合的临床前GSM研究。然而，我们还提供了证据，证明额外的化合物筛选可以发现能够打破PSEN突变的衰减效应的GSM。
P>gamma-Secretase modulators (GSMs) inhibit the generation of amyloidogenic A beta 42 peptides and are promising agents for treatment or prevention of Alzheimer's disease (AD). Recently, a second generation of GSMs with favorable pharmacological properties has emerged, but preclinical studies to assess their efficacy in vivo are lacking. Such studies rely on transgenic mouse models that express amyloid precursor protein (APP) and presenilin (PSEN) mutations associated with early-onset familial AD. Previously, we have shown that certain PSEN1 mutations attenuated the response of cultured cells to GSMs and potentially confound in vivo studies in AD mouse models. However, different combinations of familial AD mutations might have synergistic or opposing effects, and we have now systematically determined the response of APP and PSEN1 mutations present in current AD models. Using a potent acidic GSM, we found that APP mutations, either single mutations or in combination, did not affect the potency of GSMs. In contrast, all PSEN1 mutations that have been used to accelerate pathological changes in AD models strongly attenuated the A beta 42-lowering activity of GSMs with two exceptions (M146L, A246E). Similar results were obtained with potent non-acidic GSMs indicating that the attenuating effect of PSEN1 mutations cannot simply be overcome by increased potency or structural changes. Notably, two non-acidic compounds fully compensated the attenuating effect of the PSEN1-G384A mutation. Taken together, our findings indicate that most AD models with rapid pathology and advanced phenotypes are unsuitable for preclinical GSM studies. However, we also provide evidence that additional compound screens could discover GSMs that are able to break the attenuating effects of PSEN mutations.