Notch intracellular domain generation by gamma-secretase: molecular mechanisms & dependencies

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

Human evidence only

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

Where it participates (unsigned role)

Sulindac sulfide directly acts on gamma-secretase and preferentially inhibits the activity generating amyloid-beta 42 from solubilised membrane fractions in an in vitro assay using recombinant amyloid precursor protein C100 as substrate, also inhibiting generation of amyloid-beta 40 and of the Notch intracellular domain at higher concentrations, and displaying linear noncompetitive inhibition profiles for the amyloid-beta 42 generating activity.
Sulindac sulfide, the active metabolite of sulindac → The gamma-secretase complex source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/ibuprofen-research/12637581.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e0da78f88f2dfa34808abab5f1d223bdbc0372f5ea26a626b9697e0ad2255a7c", "start_char": 0, "end_char": 1209, "text_sha256": "e0da78f88f2dfa34808abab5f1d223bdbc0372f5ea26a626b9697e0ad2255a7c"}
experimental_model
In vitro gamma-secretase assay on solubilised HeLa membrane fractions with recombinant amyloid precursor protein C100
exposure
Sulindac sulfide applied to isolated gamma-secretase activity
limitations
A cell-free assay that can distinguish direct action on the enzyme from an effect on the cell. It tests sulindac sulfide rather than ibuprofen, which is recorded on the claim.
nutrient_topic
Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen
organism
Human cells
plain_language
Taken out of the cell entirely, the drug still acts on the enzyme itself, and prefers the reaction that makes the harmful fragment.
primary_references
[ibu-p12637581] Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. (2003). https://pubmed.ncbi.nlm.nih.gov/12637581/ DOI: 10.1074/jbc.m301619200
tissue_or_cell_type
Solubilised membrane fractions
Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 409–420
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In vitro gamma-secretase assay on solubilised HeLa membrane fractions with recombinant amyloid precursor protein C100 · source_derived_draft · unverified_draft
### ibu-direct-on-gamma-secretase Sulindac sulfide directly acts on gamma-secretase and preferentially inhibits the activity generating amyloid-beta 42 from solubilised membrane fractions in an in vitro assay using recombinant amyloid precursor protein C100 as substrate, also inhibiting generation of amyloid-beta 40 and of the Notch intracellular domain at higher concentrations, and displaying linear noncompetitive inhibition profiles for the amyloid-beta 42 generating activity. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: Taken out of the cell entirely, the drug still acts on the enzyme itself, and prefers the reaction that makes the harmful fragment. organism: Human cells tissue_or_cell_type: Solubilised membrane fractions experimental_model: In vitro gamma-secretase assay on solubilised HeLa membrane fractions with recombinant amyloid precursor protein C100 limitations: A cell-free assay that can distinguish direct action on the enzyme from an effect on the cell. It tests sulindac sulfide rather than ibuprofen, which is recorded on the claim. exposure: Sulindac sulfide applied to isolated gamma-secretase activity evidence_span: {"source_cache": "artifacts/ibuprofen-research/12637581.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e0da78f88f2dfa34808abab5f1d223bdbc0372f5ea26a626b9697e0ad2255a7c", "start_char": 0, "end_char": 1209, "text_sha256": "e0da78f88f2dfa34808abab5f1d223bdbc0372f5ea26a626b9697e0ad2255a7c"} [ibu-p12637581] Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. (2003). https://pubmed.ncbi.nlm.nih.gov/12637581/ DOI: 10.1074/jbc.m301619200
Complete structured claim and evidence
Ibuprofen, indomethacin and sulindac sulphide preferentially decreased the highly amyloidogenic amyloid-beta 42 peptide produced by a variety of cultured cells by as much as 80%, an effect not seen with all non-steroidal anti-inflammatory drugs and seemingly not mediated by inhibition of cyclooxygenase activity, and short-term administration of ibuprofen to mice producing mutant amyloid precursor protein lowered brain amyloid-beta 42; in cultured cells the decrease was accompanied by an increase in the amyloid-beta 1-38 isoform, indicating that these drugs subtly alter gamma-secretase activity without significantly perturbing other processing pathways or Notch cleavage.
Ibuprofen → Amyloid-beta 42, the 42-residue isoform source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/ibuprofen-research/11700559.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb9be6e821c04b48c65a999ac5852996bcb4f0249b8bd78b4454a256435e8267", "start_char": 0, "end_char": 1411, "text_sha256": "eb9be6e821c04b48c65a999ac5852996bcb4f0249b8bd78b4454a256435e8267"}
experimental_model
Cultured cells of several types and mutant amyloid precursor protein transgenic mice
exposure
Ibuprofen, indomethacin and sulindac sulphide, with short-term ibuprofen administration in vivo
limitations
The cyclooxygenase-independence is inferred from the fact that the effect is not shared by all inhibitors of the enzyme, rather than shown by a genetic control. Short-term dosing in a transgenic model.
nutrient_topic
Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen
organism
Human cells and mouse
plain_language
The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.
primary_references
[ibu-p11700559] A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. (2001). https://pubmed.ncbi.nlm.nih.gov/11700559/ DOI: 10.1038/35102591
tissue_or_cell_type
Cultured cells and brain
Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 383–394
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured cells of several types and mutant amyloid precursor protein transgenic mice · source_derived_draft · unverified_draft
### ibu-lowers-abeta42-not-via-cox Ibuprofen, indomethacin and sulindac sulphide preferentially decreased the highly amyloidogenic amyloid-beta 42 peptide produced by a variety of cultured cells by as much as 80%, an effect not seen with all non-steroidal anti-inflammatory drugs and seemingly not mediated by inhibition of cyclooxygenase activity, and short-term administration of ibuprofen to mice producing mutant amyloid precursor protein lowered brain amyloid-beta 42; in cultured cells the decrease was accompanied by an increase in the amyloid-beta 1-38 isoform, indicating that these drugs subtly alter gamma-secretase activity without significantly perturbing other processing pathways or Notch cleavage. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one. organism: Human cells and mouse tissue_or_cell_type: Cultured cells and brain experimental_model: Cultured cells of several types and mutant amyloid precursor protein transgenic mice limitations: The cyclooxygenase-independence is inferred from the fact that the effect is not shared by all inhibitors of the enzyme, rather than shown by a genetic control. Short-term dosing in a transgenic model. exposure: Ibuprofen, indomethacin and sulindac sulphide, with short-term ibuprofen administration in vivo evidence_span: {"source_cache": "artifacts/ibuprofen-research/11700559.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb9be6e821c04b48c65a999ac5852996bcb4f0249b8bd78b4454a256435e8267", "start_char": 0, "end_char": 1411, "text_sha256": "eb9be6e821c04b48c65a999ac5852996bcb4f0249b8bd78b4454a256435e8267"} [ibu-p11700559] A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. (2001). https://pubmed.ncbi.nlm.nih.gov/11700559/ DOI: 10.1038/35102591
Complete structured claim and evidence

The events it takes part in

A mechanism often involves more than two components. These are the full events, with every participant and its role.

Situations it appears in

Low-supply and faulty-machinery situations recorded in the chapters where this component plays a part.

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

Open hypotheses

Proposed ideas that involve this component. They are labeled as hypotheses and do not change any recorded statement.

This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

Notch intracellular domain generation by gamma-secretase