A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.
A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.
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DOI：
10.1186/s13195-016-0178-x
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发表时间：
2016-03-07
期刊：
影响因子：
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通讯作者：
Gobom J
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作者：
Hölttä M;Dean RA;Siemers E;Mawuenyega KG;Sigurdson W;May PC;Holtzman DM;Portelius E;Zetterberg H;Bateman RJ;Blennow K;Gobom J
在阿尔茨海默病中，大脑中的β-淀粉样肽聚集成有毒的寡聚体和斑块，这一过程与神经元退化、记忆丧失和认知能力下降有关。一种治疗策略是通过使用从淀粉样前体蛋白(APP)产生β-淀粉样蛋白的酶的抑制剂或调节剂来减少潜在有毒的β-淀粉样蛋白的产生。几个这样的候选药物因缺乏效果或不受欢迎的副作用而失败，突显了在分子水平上监测药物在大脑中的作用的重要性。在这里，我们评估脑脊液(CSF)中的多肽分析是否可以用于这一目的。15名人类健康志愿者分为三组，分别接受单剂量安慰剂或140亿毫克或280百万毫克的γ分泌酶抑制剂赛马西坦(LY450139)。在给药前和随后的6个时间点采集脑脊液中的内源性多肽，采用基于串联质量标记方法的等压标记进行相对定量，用液相色谱与质谱仪联用进行分析。在302个可重复检测到的多肽中，有11个受到治疗的影响。其中1个来自APP，1个来自淀粉样前体蛋白1。9个肽来自可能不是γ分泌酶底物，但以γ分泌酶依赖的方式调节的蛋白质。这些结果表明，脑脊液多肽方法可能是一种有价值的工具，既可以验证靶向结合，也可以确定药物的其他药效作用。数据可通过标识符为PXD003075的ProteomeXchange获得。NCT00765115,2008年9月30日注册。本文的在线版本(doi：10.1186/s13195-0160178-x)包含补充材料，授权用户可以使用。
In Alzheimer’s disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner. These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075. NCT00765115, registered 30/09/2008. The online version of this article (doi:10.1186/s13195-016-0178-x) contains supplementary material, which is available to authorized users.