Trambauer Johannes, Sarmiento Rosa Maria Rodriguez, Garringer Holly J, Salbaum Katja, Pedro Liliana D, Crusius Dennis, Vidal Ruben, Ghetti Bernardino, Paquet Dominik, Baumann Karlheinz, Lindemann Lothar, Steiner Harald
Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Feodor-Lynen-Str. 17, Munich, 81377, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Germany.
Alzheimers Res Ther. 2025 Feb 19;17(1):49. doi: 10.1186/s13195-025-01680-3.
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.
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.
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.
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.
长度为42或43个氨基酸的淀粉样β肽（Aβ）物种（Aβ42/43）引发阿尔茨海默病（AD），并由γ-分泌酶亚基早老素-1（PS1）的突变体异常产生，PS1突变体是家族性AD（FAD）的主要病因。通过γ-分泌酶调节剂（GSMs）降低这些肽越来越被认为是治疗AD的一种安全策略，因为这些化合物不会影响γ-分泌酶底物的整体切割。已表明GSMs不仅能调节野生型（WT）γ-分泌酶，还能调节FAD突变体，这扩大了它们在家族性疾病形式中的潜在用途。与大多数其他FAD突变体不同，极具侵袭性的PS1 L166P突变体对GSMs具有很大抗性。然而，这些数据大多来自过表达模型，该模型更多地模拟不太相关的纯合状态而非杂合患者情况。
用各种GSMs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，并通过免疫测定和/或基于凝胶的分析评估Aβ反应。
我们鉴定出当PS1 L166P为杂合时（如受影响患者的情况）能降低Aβ42和/或Aβ43的GSMs，并且能将致病性Aβ物种的量降低至WT水平。RO7019009是这些化合物中最有效的，既能降低致病性物种，又能同时增加短Aβ37和Aβ38，其中后者与AD进展延迟有关。另一种有效的化合物，结构新颖的吲哚型GSM RO5254601特异性作用于Aβ42产品线，导致有益的Aβ38选择性增加。有趣的是，我们进一步发现这类GSMs不仅能结合一个早老素片段，而且能结合两个，这表明它在一个不寻常的结合位点靶向γ-分泌酶。
我们的数据表明，即使是高度难治的早老素FAD突变体原则上也可用GSMs处理，这扩展了使用合适的GSM分子在FAD中进行潜在临床研究的可能性。
