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000276805 1001_ $$0P:(DE-2719)9000969$$aTrambauer, Johannes$$b0$$eFirst author$$udzne
000276805 245__ $$aγ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.
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000276805 520__ $$aAmyloid-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.
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000276805 650_7 $$2Other$$aAlzheimer’s disease
000276805 650_7 $$2Other$$aAβ
000276805 650_7 $$2Other$$aFamilial Alzheimer’s disease
000276805 650_7 $$2Other$$aPresenilin
000276805 650_7 $$2Other$$aγ-Secretase modulator
000276805 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000276805 650_7 $$2NLM Chemicals$$aPresenilin-1
000276805 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000276805 650_7 $$2NLM Chemicals$$aPeptide Fragments
000276805 650_7 $$2NLM Chemicals$$aPSEN1 protein, human
000276805 650_2 $$2MeSH$$aHumans
000276805 650_2 $$2MeSH$$aAnimals
000276805 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000276805 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000276805 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000276805 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000276805 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000276805 650_2 $$2MeSH$$aPresenilin-1: genetics
000276805 650_2 $$2MeSH$$aMutation
000276805 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000276805 650_2 $$2MeSH$$aAmyloid beta-Peptides: genetics
000276805 650_2 $$2MeSH$$aMice
000276805 650_2 $$2MeSH$$aHeterozygote
000276805 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000276805 650_2 $$2MeSH$$aPeptide Fragments: genetics
000276805 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: drug effects
000276805 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000276805 7001_ $$aSarmiento, Rosa Maria Rodriguez$$b1
000276805 7001_ $$aGarringer, Holly J$$b2
000276805 7001_ $$aSalbaum, Katja$$b3
000276805 7001_ $$0P:(DE-2719)2812527$$aPedro, Liliana Domingues$$b4
000276805 7001_ $$aCrusius, Dennis$$b5
000276805 7001_ $$aVidal, Ruben$$b6
000276805 7001_ $$aGhetti, Bernardino$$b7
000276805 7001_ $$aPaquet, Dominik$$b8
000276805 7001_ $$aBaumann, Karlheinz$$b9
000276805 7001_ $$aLindemann, Lothar$$b10
000276805 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b11$$eLast author$$udzne
000276805 773__ $$0PERI:(DE-600)2506521-X$$a10.1186/s13195-025-01680-3$$gVol. 17, no. 1, p. 49$$n1$$p49$$tAlzheimer's research & therapy$$v17$$x1758-9193$$y2025
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