ArticlePloS one2012
Presenilin is the molecular target of acidic γ-secretase modulators in living cells.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 46 citations in OpenAlex.
- 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.Alzheimer's research & therapy · 2025Article
- Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.RSC medicinal chemistry · 2020Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.The Journal of cell biology · 2019Article
- Current advances of carbene-mediated photoaffinity labeling in medicinal chemistry.RSC advances · 2018Review
- The zebrafish orthologue of familial Alzheimer's disease gene PRESENILIN 2 is required for normal adult melanotic skin pigmentation.PloS one · 2018Article
- Development of Sulfonamide Photoaffinity Inhibitors for Probing Cellular γ-Secretase.ACS chemical neuroscience · 2016Article
- Robust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.The Journal of pharmacology and experimental therapeutics · 2016Article
- Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.Molecular psychiatry · 2015Article
- Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.Molecular neurodegeneration · 2015Article
- Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans.Alzheimer's research & therapy · 2015Article
- A subset of membrane-altering agents and γ-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases.Cell reports · 2014Article
- Complex relationships between substrate sequence and sensitivity to alterations in γ-secretase processivity induced by γ-secretase modulators.Biochemistry · 2014Article
- Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.PloS one · 2014Article
- Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.International journal of Alzheimer's disease · 2014Article
- Toward the structure of presenilin/γ-secretase and presenilin homologs.Biochimica et biophysica acta · 2013Review
- Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein.Biochemistry · 2013Article
- Development and mechanism of γ-secretase modulators for Alzheimer's disease.Biochemistry · 2013Review
- γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin.The Journal of biological chemistry · 2013Article
- APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation.Stem cell reports · 2013Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC(50) of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.