{"id":"2d4f9801-d17d-532d-b98a-cdeeeead5df4","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-lowers-abeta42-not-via-cox","predicate":"reduces","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"1242c700-5e50-5f02-ad4d-51d92ccae485","mechanism_event_label":"The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.","subject":{"id":"b429f269-1d01-59f4-881a-868de0849d0d","slug":"ibuprofen","display_name":"Ibuprofen","entity_type_key":"drug"},"object":{"id":"40345ff7-8848-5083-ba88-e70ee16e7234","slug":"amyloid-beta-42","display_name":"Amyloid-beta 42, the 42-residue isoform","entity_type_key":"peptide"},"evidence_count":1,"mechanism_event":{"id":"1242c700-5e50-5f02-ad4d-51d92ccae485","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-lowers-abeta42-not-via-cox-event","event_type":"biochemical_relationship","label":"The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"a3ab59e0-0cff-5db7-b3ab-b8e7ab584d21","slug":"gamma-secretase","display_name":"The gamma-secretase complex","entity_type_key":"protein_complex"},"role":"modulated_complex","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"f2901409-f59f-5788-98a9-19e519bf02c0","slug":"amyloid-beta-38","display_name":"Amyloid-beta 1-38","entity_type_key":"peptide"},"role":"increased_product","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"a96f6ea6-2267-52fe-b909-a4c216920de8","slug":"notch-cleavage","display_name":"Notch intracellular domain generation by gamma-secretase","entity_type_key":"cellular_process"},"role":"unperturbed_process","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"320a83c1-81f2-5874-993a-d409bfb195fb","slug":"app-processing","display_name":"Amyloid precursor protein processing","entity_type_key":"cellular_process"},"role":"affected_pathway","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"c8a31ed4-f2ca-5d43-8352-e9935129a785","slug":"ptgs2","display_name":"Cyclooxygenase-2 (PTGS2)","entity_type_key":"protein"},"role":"excluded_mediator","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"21cf5948-b6ef-5eb3-b501-eee5095d513c","slug":"sulindac-sulfide","display_name":"Sulindac sulfide, the active metabolite of sulindac","entity_type_key":"small_molecule"},"role":"co_active_drug","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"b429f269-1d01-59f4-881a-868de0849d0d","slug":"ibuprofen","display_name":"Ibuprofen","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""},{"entity":{"id":"40345ff7-8848-5083-ba88-e70ee16e7234","slug":"amyloid-beta-42","display_name":"Amyloid-beta 42, the 42-residue isoform","entity_type_key":"peptide"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":7,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/ibuprofen-research/11700559.abstract.txt\", \"locator\": \"Indexed abstract; 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(2001). https://pubmed.ncbi.nlm.nih.gov/11700559/ DOI: 10.1038/35102591","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cultured cells and brain","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"fbb49a92-63c7-50f6-937e-358d87e43492","evidence_kind":"source_excerpt","locator":"Lines 383-394","start_line":383,"end_line":394,"excerpt":"### ibu-lowers-abeta42-not-via-cox\nIbuprofen, 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.\nCondition category: normal\nnutrient_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.\nplain_language: The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.\norganism: Human cells and mouse\ntissue_or_cell_type: Cultured cells and brain\nexperimental_model: Cultured cells of several types and mutant amyloid precursor protein transgenic mice\nlimitations: 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.\nexposure: Ibuprofen, indomethacin and sulindac sulphide, with short-term ibuprofen administration in vivo\nevidence_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\"}\n[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","model_system":"Cultured cells of several types and mutant amyloid precursor protein transgenic mice","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"31c4939d-f520-55c0-973b-224743caf245","stable_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"cc2b388178f97f5906b66ecbe441fc5c86d51fd645947c5260fb0b4bdb4bcd21","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"eaf4bb97-9b9b-5b6f-896a-86110dd6bfcc","title":"By what route does ibuprofen lower amyloid-beta 42?","kind":"qualification","status":"open","why":"Three mechanisms are proposed in this collection and they are not the same. The original report attributed the effect to a subtle alteration of gamma-secretase activity, shifting production from amyloid-beta 42 toward amyloid-beta 38 without perturbing Notch cleavage, and showed it was not shared by all cyclooxygenase inhibitors. A study of the enantiomers found that R-ibuprofen, which barely inhibits cyclooxygenase, lowers the peptide, and explicitly excluded nuclear factor kappa B inhibition as the mediator even though the R enantiomers do inhibit that factor. A third route runs through peroxisome proliferator-activated receptor gamma to RhoA, with receptor knockdown and selective antagonism both abolishing the effect on RhoA and neurite growth. A cell-free assay of a related drug shows direct noncompetitive action on gamma-secretase itself. These are not mutually exclusive and the records do not weigh them against each other. What is agreed is that the route is not cyclooxygenase inhibition.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 14:28:23","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/eaf4bb97-9b9b-5b6f-896a-86110dd6bfcc","sides":[{"conflict_id":"eaf4bb97-9b9b-5b6f-896a-86110dd6bfcc","ordinal":0,"label":"The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","start_line":383,"end_line":394,"quote":"### ibu-lowers-abeta42-not-via-cox\nIbuprofen, 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.\nCondition category: normal\nnutrient_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.\nplain_language: The drug shifts where an enzyme cuts rather than stopping it, and the sticky fragment is replaced by a shorter harmless one.\norganism: Human cells and mouse\ntissue_or_cell_type: Cultured cells and brain\nexperimental_model: Cultured cells of several types and mutant amyloid precursor protein transgenic mice\nlimitations: 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.\nexposure: Ibuprofen, indomethacin and sulindac sulphide, with short-term ibuprofen administration in vivo\nevidence_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\"}\n[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","source_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","source_title":"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)","claim_ids":["2d4f9801-d17d-532d-b98a-cdeeeead5df4"]},{"conflict_id":"eaf4bb97-9b9b-5b6f-896a-86110dd6bfcc","ordinal":1,"label":"The half of the molecule that cannot block cyclooxygenase is the half that lowers the Alzheimer peptide.","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","start_line":396,"end_line":407,"quote":"### ibu-r-enantiomer-lowers-abeta42\nR-ibuprofen and R-flurbiprofen, with poor cyclooxygenase-inhibiting activity, reduce amyloid-beta 42 production by human cells, and although these R enantiomers inhibit nuclear factor kappa B activation and that factor can selectively regulate amyloid-beta 42, the reduction is not mediated by inhibition of nuclear factor kappa B activation; clinical use of these drugs for Alzheimer’s disease has been hampered by dose-limiting toxicity believed to be due to cyclooxygenase inhibition, which is reportedly not essential for selective amyloid-beta 42 reduction.\nCondition category: biomarker_context\nnutrient_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.\nplain_language: The half of the molecule that cannot block cyclooxygenase is the half that lowers the Alzheimer peptide.\norganism: Human cells\ntissue_or_cell_type: Cultured cells\nexperimental_model: Human cells treated with single enantiomers of ibuprofen and flurbiprofen\nlimitations: Uses the enantiomer as the control for cyclooxygenase involvement, which is cleaner than comparing different drugs. It also rules out the nuclear factor kappa B route explicitly.\nexposure: R-ibuprofen and R-flurbiprofen, chosen for their poor cyclooxygenase-inhibiting activity\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/12421374.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"bb022923aad1deb90ae4c540e3e8aab4080a3b78aa9c4a9356447385c31e9c8b\", \"start_char\": 0, \"end_char\": 1003, \"text_sha256\": \"bb022923aad1deb90ae4c540e3e8aab4080a3b78aa9c4a9356447385c31e9c8b\"}\n[ibu-p12421374] Selective inhibition of Abeta42 production by NSAID R-enantiomers. (2002). https://pubmed.ncbi.nlm.nih.gov/12421374/ DOI: 10.1046/j.1471-4159.2002.01195.x","source_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","source_title":"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)","claim_ids":["64d96cfb-c288-5a83-9f4c-ec4f73b757fe"]},{"conflict_id":"eaf4bb97-9b9b-5b6f-896a-86110dd6bfcc","ordinal":2,"label":"The drug reaches a growth-blocking switch in neurons through a fat-sensing receptor, not through prostaglandins.","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","start_line":422,"end_line":433,"quote":"### ibu-pparg-couples-to-rhoa\nIbuprofen activates peroxisome proliferator-activated receptor gamma in neuron-like PC12 and B104 cells, activation with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen and promotes neurite elongation in primary neurons exposed to axonal growth inhibitors, small interfering RNA against the receptor blocks RhoA suppression by those agonists, and selective receptor inhibition prevents the effect of ibuprofen on RhoA activity and neurite growth, supporting an essential role for the receptor in coupling ibuprofen to RhoA inhibition.\nCondition category: normal\nnutrient_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.\nplain_language: The drug reaches a growth-blocking switch in neurons through a fat-sensing receptor, not through prostaglandins.\norganism: Rat\ntissue_or_cell_type: Neurons\nexperimental_model: Neuron-like PC12 and B104 cells and primary cultured neurons with small interfering RNA knockdown\nlimitations: The knockdown and the selective antagonist together make the receptor requirement a test rather than a correlation. Cell lines and primary culture rather than an animal.\nexposure: Ibuprofen with peroxisome proliferator-activated receptor gamma agonists, antagonists and knockdown\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/20089905.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"77e2dbb010dcee44bd66645ec26cb844d7041ea4930f6373ae5dd6b10da37df3\", \"start_char\": 0, \"end_char\": 1812, \"text_sha256\": \"77e2dbb010dcee44bd66645ec26cb844d7041ea4930f6373ae5dd6b10da37df3\"}\n[ibu-p20089905] A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. (2010). https://pubmed.ncbi.nlm.nih.gov/20089905/ DOI: 10.1523/jneurosci.5045-09.2010","source_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","source_title":"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)","claim_ids":["d73c17cf-defd-5dff-b687-7b7439ba4338"]}]}],"corrections":[],"research":null}