Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.
Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.
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DOI：
10.1001/jamaneurol.2014.2482
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发表时间：
2014-12
期刊：
影响因子：
29
通讯作者：
Yuan, Shauna H.
中科院分区：
文献类型：
--
作者：
Liu, Qing;Waltz, Shannon;Woodruff, Grace;Ouyang, Joe;Israel, Mason A.;Herrera, Cheryl;Sarsoza, Floyd;Tanzi, Rudolph E.;Koo, Edward H.;Ringman, John M.;Goldstein, Lawrence S. B.;Wagner, Steven L.;Yuan, Shauna H.
尽管已经花费了相当大的努力来开发用于阿尔茨海默病的候选药物，但是由于缺乏功效或安全性问题，还没有一种药物成功。目前阿尔茨海默病药物发现和开发方法的一个潜在缺点是，它们主要依赖于大量过表达野生型或突变蛋白的转化细胞系和动物模型。到目前为止，药物开发失败的部分原因可能是这些方法的局限性，这些方法不能准确地揭示候选药物在幼稚人类神经元细胞中的行为。分析来自携带3种不同早老素1（PS1）突变的患者和无任何过表达的非痴呆对照个体的人诱导多能干细胞的纯化神经元。我们测试了γ-分泌酶抑制剂和γ-分泌酶调节剂（GSM）在来自正常对照和3种PS1突变（A246 E、H163 R和M146 L）的神经元中的功效。成人皮肤活组织检查从阿尔茨海默病研究中心，加州大学，圣地亚哥的志愿者获得。用γ-分泌酶抑制剂或GSM处理细胞培养物。比较了溶剂处理培养物与药物处理培养物之间培养基中总β-淀粉样蛋白（Aβ）和Aβ肽38、40和42的含量。通过酶联免疫吸附试验测定培养基中的可溶性Aβ水平。正如预测的那样，突变型PS1神经元在基础状态下与非痴呆对照神经元相比，Aβ42：Aβ40比值升高（P <0.05）。用一种有效的非甾体抗炎药如GSM进行治疗，揭示了一种新的生物标志物特征，该特征不同于所有以前测试的细胞类型和动物。这种新的特征在突变体和对照神经元中是相同的，包括Aβ42、Aβ40和Aβ38以及Aβ42：Aβ40比率的降低，而总Aβ水平没有变化。这种生物标志物的差异可能是由于转化细胞模型中淀粉样前体蛋白的过度表达。我们的研究结果表明，用这种模型获得的生物标志物特征是误导性的，并且来自人诱导多能干细胞的人神经元提供了一种独特的特征，其将更准确地反映人类患者的药物反应和GSM治疗期间观察到的脑脊液生物标志物变化。
Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells. To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L). Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures. Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay. As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P <.05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non–nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels. This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
--
作者：
Peng, Jun;Liu, Qiuyue;Zeng, Xianmin
通讯作者：
Zeng, Xianmin
影响因子：
46.9
作者：
Chambers, Stuart M.;Fasano, Christopher A.;Papapetrou, Eirini P.;Tomishima, Mark;Sadelain, Michel;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
5.3
作者：
Mitani, Yasuyuki;Yarimizu, Junko;Matsuoka, Nobuya
通讯作者：
Matsuoka, Nobuya
影响因子：
5.3
作者：
Takami, Mako;Nagashima, Yu;Ihara, Yasuo
通讯作者：
Ihara, Yasuo