γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Johannes Trambauer, Rosa Maria Rodriguez Sarmiento, Holly J Garringer, Katja Salbaum, Liliana D Pedro, Dennis Crusius, Ruben Vidal, Bernardino Ghetti, Dominik Paquet, Karlheinz Baumann, Lothar Lindemann, Harald Steiner
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引用次数: 0

Abstract

Background: Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced in abnormal amounts by mutants of the γ-secretase subunit presenilin-1 (PS1), which represent the primary cause of familial AD (FAD). Lowering these peptides by γ-secretase modulators (GSMs) is increasingly considered a safe strategy to treat AD since these compounds do not affect the overall cleavage of γ-secretase substrates. GSMs were shown to modulate not only wild-type (WT) γ-secretase but also FAD mutants, expanding their potential use also to the familial form of the disease. Unlike most other FAD mutants, the very aggressive PS1 L166P mutant is largely resistant to GSMs. However, these data were mostly obtained from overexpression models, which mimic more the less relevant homozygous state rather than the heterozygous patient situation.

Methods: Mouse embryonic fibroblast and induced pluripotent stem cell-derived neuronal PS1 L166P knock-in (KI) cell models were treated with various GSMs and Aβ responses were assessed by immunoassays and/or gel-based analysis.

Results: We identified GSMs that lower Aβ42 and/or Aβ43 when PS1 L166P is heterozygous, as it is the case in affected patients, and could reduce the amount of pathogenic Aβ species towards WT levels. RO7019009 was the most potent of these compounds, reducing both pathogenic species and concomitantly increasing the short Aβ37 and Aβ38, of which the latter has been associated with delayed AD progression. Another effective compound, the structurally novel indole-type GSM RO5254601 specifically acts on the Aβ42 product line leading to a selective increase of the beneficial Aβ38. Interestingly, we further found that this class of GSMs can bind not only one, but both presenilin fragments suggesting that it targets γ-secretase at an unusual binding site.

Conclusion: Our data show that even highly refractory presenilin FAD mutants are in principle tractable with GSMs extending the possibilities for potential clinical studies in FAD with suitable GSM molecules.

一种侵袭性阿尔茨海默病早老素突变体的γ-分泌酶调节剂耐药性可以通过一组高级化合物在杂合患者状态下克服。
背景:长度为42或43个氨基酸的淀粉样蛋白-β肽(Aβ42/43)可引发阿尔茨海默病(AD),并且由γ-分泌酶亚基早老素-1 (PS1)突变体产生异常量,这是家族性AD (FAD)的主要原因。由于γ-分泌酶调节剂(GSMs)不影响γ-分泌酶底物的整体切割,因此越来越多的人认为用GSMs降低这些肽是治疗AD的一种安全策略。研究表明,GSMs不仅可以调节野生型(WT) γ-分泌酶,还可以调节FAD突变体,从而将其潜在用途扩展到该疾病的家族形式。与大多数其他FAD突变体不同,极具侵袭性的PS1 L166P突变体在很大程度上对gsm具有抗性。然而,这些数据大多来自过表达模型,这些模型更多地模拟不太相关的纯合子状态,而不是杂合子患者的情况。方法:采用多种gsm处理小鼠胚胎成纤维细胞和诱导多能干细胞衍生的神经元PS1 L166P敲入(KI)细胞模型,通过免疫测定和/或凝胶分析评估Aβ反应。结果:我们发现,当PS1 L166P是杂合的时候,GSMs可以降低Aβ42和/或Aβ43,就像在受影响的患者中一样,并且可以将致病性Aβ物种的数量减少到WT水平。RO7019009是这些化合物中最有效的,可以减少致病物种,同时增加短的a - β37和a - β38,其中a - β37和a - β38与延迟AD进展有关。另一种有效化合物,结构新颖的吲哚型gsmro5254601特异性作用于a - β42产品线,导致有益的a - β38选择性增加。有趣的是,我们进一步发现这类gsm不仅可以结合一个,而且可以结合两个早老素片段,这表明它在一个不寻常的结合位点靶向γ-分泌酶。结论:我们的数据表明,即使是高度难治性的早老素FAD突变体,原则上也可以用GSM分子处理,这扩大了使用合适的GSM分子进行FAD临床研究的可能性。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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