Cited by 1,388Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

Weggen, Sascha, Eriksen, Jason L., Das, Pritam, Sagi, Sarah A., Wang, Rong, Pietrzik, Claus U., Findlay, Kirk A., Smith, Tawnya E., Murphy, Michael P., Bulter, Thomas, Kang, David E., Marquez-Sterling, Numa, Golde, Todd E., Koo, Edward H.·2001·Nature

DOI 10.1038/35102591

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Abstract

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant beta-amyloid precursor protein (APP) lowered their brain levels of Abeta42. In cultured cells, the decrease in Abeta42 secretion was accompanied by an increase in the Abeta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Abeta42 peptide levels independently of COX activity and that this Abeta42-lowering activity could be optimized to selectively target the pathogenic Abeta42 species.

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Inflammation and Alzheimer’s disease
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“Ibuprofen treatment of Tg2576 transgenic mice Female Tg2576 mice overexpressing APP695 containing the ‘Swedish’ mutation were treated at 3 months old, when they show high levels of soluble Aβ in brain but no signs of Aβ depositio”
Background
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“However, in 2001 Weggen et al. first reported that NSAIDs selectively lower the level of Ab independently of cyclooxygenase inhibition (Weggen et al. 2001): only a subset of NSAIDs (collectively termed SALAs) and the cyclooxygenase-inactive R-flurbiprofen lowered the level of Ab (Eriksen et al.…”
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Background
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“In addition to their anti-inflammatory activities [14,15], ibuprofen affects the amyloid pathology in the brain [16] and its long-term use has been associated with reduced risk of neurodegeneration [17].”
Background
Does wine prevent dementia?
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“85 Flurizan, the R-enantiomer of ﬂ urbiprofen, is in clinical phase III trials for the treatment of AD.”
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“Recent studies have identified novel classes of inhibitors that specifically target Ab42 and reduce its levels [Weggen et al., 2001].”
BackgroundInfluential
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Abdel‐Aal, R. A., Hussein, O. A., Elsaady, R. G., & Abdelzaher, L. A. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174695 · Cited by 17
Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells
Rennhack, A., Jumpertz, T., Neß, J., Baches, S., Pietrzik, C. U., Weggen, S., & Bulic, B. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2012.08.034 · Cited by 14
Self-citation
Efficient four‐drug cocktail therapy targeting amyloid‐β peptide for Alzheimer's disease
Asai, M., Iwata, N., Tomita, T., Iwatsubo, T., Ishiura, S., Saido, T. C., & Maruyama, K. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22503 · Cited by 15
“Beyond that, these NSAIDs have no effect on Notch processing (Weggen et al., 2001); consequently, they represent a promising therapeutic agent for AD (Kukar and Golde, 2008).”
BackgroundMethodResultInfluential
Fighting fire with fire: The immune system might be key in our fight against Alzheimer’s disease
Dujardin, P., Vandenbroucke, R. E., & Hoecke, L. V. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.01.004 · Cited by 14
Inhibition of γ-secretase by the CK1 inhibitor IC261 does not depend on CK1δ
Höttecke, N., Liebeck, M., Baumann, K., Schubenel, R., Winkler, E., Steiner, H., & Schmidt, B. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.02.110 · Cited by 14
An improved cell-based method for determining the γ-secretase enzyme activity against both Notch and APP substrates
McKee, T. D., Loureiro, R. M. B., Dumin, J. A., Zarayskiy, V. V., & Tate, B. A. (2012) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2012.11.011 · Cited by 14
MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease
Pohland, M., Hagl, S., Pellowska, M., Wurglics, M., Schubert‐Zsilavecz, M., & Eckert, G. P. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1765-0 · Cited by 14
Novel Approaches to Treatment of Autoimmune Neuroinflammation and Lessons for Drug Development
Nizri‏, E., Irony-Tur-Sinai, M., Grigoriadis, N., Abramsky, O., Amitai, G., & Brenner, T. (2006) · Pharmacology · doi:10.1159/000097628 · Cited by 14
“IBU was previously shown to reduce the production of insoluble β-amyloid peptide although not by COX inhibition [”
Background
Modulators and Inhibitors of γ- and β-Secretases
Schmidt, B., Baumann, S., Narlawar, R., Braun, H. A., & Larbig, G. (2006) · Neurodegenerative Diseases · doi:10.1159/000095269 · Cited by 14
“IC 50 values for Aβ 40 , Aβ 42 and AICD were recently reported to be ∼75 μ M . The generation of NICD-Flag was not inhibited, even at >10-fold concentrations. Selected nonsteroidal anti-inflammatory drugs (NSAIDs) reduce Aβ production without affecting alternative cleavages [”
Background
The Role of Aβ-Peptide on Spatial Memory, EEG, Auditory Evoked Potentials And Nicotinic Cholinergic Receptors in A/P Transgenic Mice
Wang, J. (2003) · Cited by 14
Field amplified sample stacking of amyloid beta (1-42) oligomers using capillary electrophoresis
Paracha, S., & Hestekin, C. N. (2016) · Biomicrofluidics · doi:10.1063/1.4954051 · Cited by 13
Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators
Gerlach, K., Hobson, S., Eickmeier, C., Groß, U., Braun, C., Sieger, P., Garneau, M., Hoerer, S., & Heine, N. B. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.04.053 · Cited by 13
Design and optimization of tricyclic gamma-secretase modulators
Shi, J., Zuev, D., Xu, L. J., Lentz, K. A., Grace, J. E., Toyn, J. H., Olson, R. E., Macor, J. E., & Thompson, L. A. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.06.020 · Cited by 13
Neuroinflammation and oxidative injury in developmental neurotoxicity
Milatović, D., Zaja‐Milatovic, S., BREYER, R. M., Aschner, M., & Montine, T. J. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-382032-7.10064-5 · Cited by 13
Interaction of naproxen amphiphilic derivatives with biomembrane models evaluated by differential scanning calorimetry and Langmuir–Blodgett studies
Micieli, D., Giuffrida, M. C., Pignatello, R., Castelli, F., & Sarpietro, M. G. (2011) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2011.04.092 · Cited by 13
Antimalarials Inhibit Human Erythrocyte Membrane Acetylcholinesterase
Katewa, S. D., & Katyare, S. S. (2005) · Drug and Chemical Toxicology · doi:10.1080/01480540500262912 · Cited by 13
“Moreover, NSAIDs dramatically reduce the secretion of Ab1–42 in cells in vitro (Citron, 2004; Morihara et al., 2002; Weggen et al., 2001; Zhou et al., 2003).”
Background
1,2‐Diaryl‐2‐hydroxyiminoethanones as Dual COX ‐1 and β‐Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study
Irannejad, H., Tan, O. Ü., Ozadali‐Sari, K., Dadashpour, S., Küçükkılınç, T. T., Ahangar, N., Ahmadnejad, M., & Emami, S. (2014) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12435 · Cited by 13
Identification and Preclinical Pharmacology of the γ -Secretase Modulator BMS-869780
Toyn, J. H., Thompson, L. A., Lentz, K. A., Meredith, J. E., Burton, C. R., Sankaranararyanan, S., Guss, V. L., Hall, T., Iben, L. G., Krause, C., et al. (2014) · International Journal of Alzheimer s Disease · doi:10.1155/2014/431858 · Cited by 13
“The discovery and evaluation of BMS-869780 started with a high-throughput screen of the BMS compound inventory to identify selective inhibitors of A𝛽1-42 in cell cultures and ended with predictions for human dose and exposure margins for off-target activity and safety.”
Method
Association Between Non-Steroidal Anti-Inflammatory Drug Use and Cognitive Decline: A Systematic Review and Meta-Analysis of Prospective Cohort Studies
Wang, W., Sun, Y., & Zhang, D. (2016) · Drugs & Aging · doi:10.1007/s40266-016-0379-9 · Cited by 13
“Finally, increasing evidence suggests that a key event in the pathogenesis of cognitive decline is the altered production, aggregation, and deposition of the Ab peptide, and NSAIDs may directly reduce Ab42 peptide levels [20].”
Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators
Zhao, Z., Pissarnitski, D. A., Huang, X., Palani, A., Zhu, Z., Greenlee, W. J., Hyde, L. A., Song, L., Terracina, G., Zhang, L., et al. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00178 · Cited by 13
Decreased microglial numbers in Vav1-Cre + :dicer knock-out mice suggest a second source of microglia beyond yolk sac macrophages
Fehrenbach, M. K., Tjwa, M., Bechmann, I., & Krueger, M. (2018) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2018.03.004 · Cited by 14
Repeated performance of spatial memory tasks ameliorates cognitive decline in APP/PS1 mice
Lonnemann, N., Körte, M., & Hosseini, S. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114218 · Cited by 12
Medications and Diet
Kawas, C. H. (2006) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200607001-00014 · Cited by 15
“In vitro studies have suggested that a subset of these drugs (ibuprofen, sulindac, and indomethacin) can decrease Ab 42 levels in cultured cells and the effect is not mediated by COX inhibition.(11)”
Background
Patents targeting γ-secretase inhibition and modulation for the treatment of Alzheimer's disease: 2004 – 2008
Garofalo, A. W. (2008) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.18.7.693 · Cited by 13
“This decrease in A β 42 was shown to be independent of COX activity and was accompanied by a dose-dependent increase in A β 38, a less amyloidogenic isoform [58] .”
Background
Tetrabutylammonium fluoride-promoted α-[11C]methylation of α-arylesters: a simple and robust method for the preparation of 11C-labeled ibuprofen
Kato, K., Kikuchi, T., Nengaki, N., Arai, T., & Zhang, M. (2010) · Tetrahedron Letters · doi:10.1016/j.tetlet.2010.09.007 · Cited by 13
Cyclooxygenase as a Target for the Antiamyloidogenic Activities of Nonsteroidal Anti-Inflammatory Drugs in Alzheimer’s Disease
Pasinetti, G. M. (2002) · Neurosignals · doi:10.1159/000067428 · Cited by 13
Therapeutics and Mild Cognitive Impairment
Thal, L. J. (2003) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200304002-00012 · Cited by 13
Tarenflurbil: a shot on goal
Aisen, P. S. S. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70091-7 · Cited by 13
Amino‐terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains
Wirths, O., Lehnen, C., Fricke, M., Talucci, I., Klafki, H., Morgado, B., Lehmann, S., Münch, C., Liepold, T., Wiltfang, J., et al. (2024) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12991 · Cited by 14
Self-citation
Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer’s Disease
Li, J., Ma, X., Wang, Y., Chen, C., Hu, M., Wang, L., Fu, J., Shi, G., Zhang, D., & Zhang, T. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00085 · Cited by 12
“A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity.”
Background
Reactive Centers of Curcumin and the Possible Role of Metal Complexes of Curcumin as Antioxidants
Priya, R. S., Balachandran, S., Daisy, J., & Mohanan, P. V. (2015) · Universal Journal of Physics and Application · doi:10.13189/ujpa.2015.030102 · Cited by 12
“Curcumin exhibit unique charge and bonding characteristic [13] that facilitate penetration into the blood brain barrier superior to other known nonsteroidal anti-inflammatory drug (NSAID)[14] and Congo red[15].”
Background
The use of nitrous oxide in paediatric anaesthetic practice in the United Kingdom: a questionnaire survey*
Sheraton, T. E., Gildersleve, C. D., & Hall, J. E. (2006) · Anaesthesia · doi:10.1111/j.1365-2044.2006.04857.x · Cited by 13
Expression of proteins linked to Alzheimer’s disease in C6 rat glioma cells under the action of lipopolysaccharide (LPS), nimesulide, resveratrol and citalopram
Martínez-Díaz, J. A., Hernández‐Aguilar, M. E., Rojas-Durán, F., Herrera‐Covarrubias, D., García, L. I., Mestizo-Gutiérrez, S. L., & Aranda-Abreu, G. E. (2020) · Turkish Journal of Biochemistry · doi:10.1515/tjb-2020-0091 · Cited by 12
“As for the effect of non-steroidal anti-inflammatory drugs on APP processing, ibuprofen has been reported to inhibit gamma-secretase, thereby reducing β-amyloid production by an independent mechanism of COX-2 [36] in our study we found that nimesulide is capable of decreasing BACE1 expression, but not citalopram and r…”
Background
Humoral immune responses to peptides derived from the β-amyloid peptide C-terminal sequence
Miller, D. L., Potempska, A., & Mehta, P. D. (2007) · Amyloid · doi:10.1080/13506120601116500 · Cited by 12
“These antibodies are also useful to discover and evaluate therapeutic agents that inhibit Ab42 production or aggregation [25].”
Background
γ-Secretase inhibitors: still in the running as Alzheimer’s therapeutics
Marjaux, E., & Strooper, B. D. (2004) · Drug Discovery Today Therapeutic Strategies · doi:10.1016/j.ddstr.2004.05.001 · Cited by 12
NSAID-derived γ-secretase modulators. Part III: Membrane anchoring
Baumann, S., Höttecke, N., Schubenel, R., Baumann, K., & Schmidt, B. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.10.035 · Cited by 12
Mode of Administration-Dependent Brain Uptake of Indomethacin: Sustained Systemic Input Increases Brain Influx
Dahan, A., & Hoffman, A. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.011817 · Cited by 12
“Indomethacin inhibits amyloid plaque formation via -secretase inhibition, which is a cyclooxygenase-independent process (Weggen et al., 2001).”
Background
La Lunga Attesa : Towards a Molecular Approach to Neuroimaging and Therapeutics in Alzheimer's Disease
Villemagne, V. L., Ng, S., Cappai, R., Barnham, K. J., Fodero‐Tavoletti, M. T., Rowe, C. C., & Masters, C. L. (2006) · The Neuroradiology Journal · doi:10.1177/197140090601900406 · Cited by 12
Chapter 5. Secretase inhibitors for Alzheimer's disease
Kornilova, A. Y., & Wolfe, M. S. (2003) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(03)38006-6 · Cited by 12
Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease Progression: A Randomized Controlled Trial
Aisen, P. S., Schafer, K. A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K. L., Farlow, M. R., Jin, S., Thomas, R. G., Thal, L. J., et al. (2003) · JAMA · doi:10.1001/jama.289.21.2819 · Cited by 5
“The nonsignificant results with naproxen could be explained by an insufficient dose; alternatively, other drugs in this same class, such as ibuprofen, may have greater activity in AD mediated by an effect on processing of the amyloid precursor protein.(24) Rofecoxib, 1 of 2 available selective COX-2 inhibitors at the…”
Background

Authors: Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., Kang, D. E., Marquez-Sterling, N., Golde, T. E., & Koo, E. H.
Affiliations: University of California San Diego (US)
Mayo Clinic (US)
Icahn School of Medicine at Mount Sinai (US)
Northwestern University (US)
Corresponding author: Koo, Edward H.
ORCID: Weggen, Sascha
Eriksen, Jason L.
Das, Pritam
Wang, Rong
Pietrzik, Claus U.
Kang, David E.
Golde, Todd E.
Koo, Edward H.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-11
Volume: 414
Issue: 6860
Pages: 212-216
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35102591
OpenAlex: W2113690827
Cited by: 1,388
References: 30
Citations by year: 2026: 14 · 2025: 11 · 2024: 18 · 2023: 21 · 2022: 24 · 2021: 26 · 2020: 35 · 2019: 29 · 2018: 24 · 2017: 44 · 2016: 55 · 2015: 34 · 2014: 58 · 2013: 60 · 2012: 69
FWCI: 53.21
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: nonsteroidal anti-inflammatory drugs, amyloid-beta 42, Alzheimer's disease, ibuprofen, indomethacin, cyclooxygenase-independent mechanism, amyloid precursor protein, Notch cleavage, neuroinflammation, amyloid pathology
MeSH terms: Alzheimer Disease, Animals, Anti-Inflammatory Agents, Non-Steroidal, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Cricetinae, Humans, Ibuprofen, Indomethacin, Mice, Transgenic, Peptide Fragments, Endopeptidases, Prostaglandin-Endoperoxide Synthases, Mass Spectrometry, Sulindac, Tumor Cells, Cultured, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, CHO Cells, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases

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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

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