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
Clinical trial of indomethacin in Alzheimer's disease
Rogers, J., Kirby, L., Hempelman, S. R., Berry, D. A., McGeer, P. L., Kaszniak, A. W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., et al. (1993) · Neurology · doi:10.1212/wnl.43.8.1609 · Cited by 991
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Selected Non-steroidal Anti-inflammatory Drugs and Their Derivatives Target γ-Secretase at a Novel Site
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“, respectively. We also examined the effect of a non-steroidal anti-inflammatory drug (NSAID), sulindac sulfide”
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Butterfield, D. A., Griffin, S. T., Münch, G. W., & Pasinetti, G. M. (2002) · Journal of Alzheimer s Disease · doi:10.3233/jad-2002-4309 · Cited by 176
“Interestingly, recent studies suggested that non selective COX inhibitors may preferentially decrease the levels of the highly amyloidogenic Aβ42 peptide (the 42-residue isoform of the amyloidβ peptide) produced from a variety of cultured cells and that some NSAIDs (sulindac) uses a novel mechanisms independently of C…”
Curcumin‐Derived Pyrazoles and Isoxazoles: Swiss Army Knives or Blunt Tools for Alzheimer's Disease?
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Self-citation
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“(1) Furthermore, the effect of these NSAIDs on Aβ modulation was dissociated from their COX activity.(1) GSMs have many unique characteristics, which include: 1) reducing Aβ42 production; 2) promoting shorter forms of Aβ species (Aβ38 or Aβ37); 3) having no significant effect on the total amount of Aβ produced nor acc…”
BackgroundInfluential
Recovery of Cognitive Function After Remifentanil-Propofol Anesthesia: A Comparison with Desflurane and Sevoflurane Anesthesia
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“The significant reduction of A42 and the increase in the ratio of A1–38:A1– 42 in 5LO knockout mice would suggest the involvement of -secretase ( 37 , 38).”
Background
In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile
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“Indeed, several NSAIDs, including ibuprofen, sulindac sulphide, and indomethacin could decrease the levels of secreted A 42 [108,54,109].”
Background
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“APP gene expression and processing is regulated by NF- B as an injury-responsive cytokine/neurotrophic factor (Mattson and Camandola, 2001; Weggen et al., 2001) (see Section 10.3).”
BackgroundInfluential
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Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead
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“[110] Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al.”
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The Endogenous Estrogen Status Regulates Microglia Reactivity in Animal Models of Neuroinflammation
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“reported that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ-42 peptide produced from a variety of cultured cells by as much as 80% [79].”
Background
Peroxisome Proliferator-Activated Receptor γ Induces a Clearance Mechanism for the Amyloid-β Peptide
Espuny-Camacho, I., Serneels, L., Spittaels, K., Merchiers, P., Dominguez, D. I., & Strooper, B. D. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3987-04.2004 · Cited by 171
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“The mechanism is presumably through a subtle effect on γ-secretase, which does not seem to affect Notch processin”
Design, Synthesis, and Structure−Activity Relationships of Alkylcarbamic Acid Aryl Esters, a New Class of Fatty Acid Amide Hydrolase Inhibitors
Tarzia, G., Duranti, A., Tontini, A., Piersanti, G., Mor, M., Rivara, S., Plazzi, P. V., Park, C., Kathuria, S., & Piomelli, D. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm021119g · Cited by 167
The Proton-Pump Inhibitor Lansoprazole Enhances Amyloid Beta Production
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“being classified as straight GSMs when they lower Ab42 and rise Ab38 [41], or as inverse GSMs (iGSM) when they do the opposite [39,42,43].”
Background
Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease
Zhao, J., Liu, X., Xia, W., Zhang, Y., & Wang, C. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00137 · Cited by 178
“Numerous studies have shown that Aβ aggregates, especially soluble oligomers, impair both synaptic function and structure (Kokubo et al., 2005; Wilcox et al., 2011).”
Background
γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs
Oehlrich, D., Berthelot, D., & Gijsen, H. J. M. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm101168r · Cited by 163
The physiology of the β‐amyloid precursor protein intracellular domain AICD
Pardossi‐Piquard, R., & Checler, F. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07475.x · Cited by 159
“Accordingly, non-steroidal anti-inflammatory drugs (Weggen et al. 2001), the antidepressant agent lithium (Phiel et al. 2003), and the tyrosine kinase inhibitor imatinib (gleevec) (Netzer et al. 2003), all inhibit Ab production without affecting NICD production.”
γ-Secretase Exists on the Plasma Membrane as an Intact Complex That Accepts Substrates and Effects Intramembrane Cleavage*
Chyung, J. H., Raper, D. M. S., & Selkoe, D. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409272200 · Cited by 158
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“A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) was the first GSM compounds identified (Weggen et al., 2001).”
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Antioxidant Therapy in Alzheimers Disease: Theory and Practice
Aliev, G., Obrenovich, M. E., Reddy, V. P., Shenk, J. C., Moreira, P. I., Nunomura, A., Zhu, X., Smith, M. A., & Perry, G. L. (2008) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955708786369582 · Cited by 160
“AD was also found to be less frequent among individuals who used anti-inflammatory drugs [84].”
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Microglia change from a reactive to an age-like phenotype with the time in culture
Caldeira, C., Oliveira, A. F., Cunha, C., Vaz, A. R., FalcÃ£o, A. S., Fernandes, A., & Brites, D. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00152 · Cited by 156
“Age-related CNS disorders have been related with chronic and progressive neuronal loss but also with chronic mild neuroinflammation involving activated/primed microglia (Maezawa et al., 2011; Williamson et al., 2011).”
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Notch Inhibition as a Promising New Approach to Cancer Therapy
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“On the other hand, non-steroidal anti-inflammatory drugs such as sulindac sulfide, ibuprofen, indomethacin and flurbiprofen, which specifically lower Aβ42 levels without affecting Aβ40 production [ 84 ], decrease the proximity of PS1 N- and C-terminus and PS1 to APP C-terminus [85].”
Gallic acid, a histone acetyltransferase inhibitor, suppresses β‐amyloid neurotoxicity by inhibiting microglial‐mediated neuroinflammation
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Dementia Prevention: Methodological Explanations for Inconsistent Results
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“Also, there have been studies of NSAID use among arthritis patients that have indicated that these drugs reduce the risk of AD [61]; although this finding suggests a way to counter genetic risk associated with AD [63], rather than speaking against genetic causation.”
Combined CSF tau, p-tau181 and amyloid-β 38/40/42 for diagnosing Alzheimer’s disease
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“…distributions of different Ab species are regulated within very narrow limits (Wiltfang et al. 2002; Bibl et al. 2007a; Wiltfang et al. 2007) (4) Distinct g-secretase activities may be reflected most adequately by the ratio Ab1-42/Ab1-40 Wiltfang et al. 2001) or Ab1-38/Ab1-40 (Weggen et al. 2001).”
Background
Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein
Berezovska, O., Lleó, A., Herl, L. D., Frosch, M. P., Stern, E. A., Bacskai, B. J., & Hyman, B. T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0364-05.2005 · Cited by 150
“, 2004b), that the proximity of the PS1 NT to the PS1 CT and of the PS1 loop to the APP CT, are altered by nonsteroidal anti-inflammatory drugs (NSAIDs) that lower A 42 (Weggen et al., 2001).”
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“Weggen et al. [101] have suggested that the reduction of A β 42 peptides is not mediated by inhibition of cyclooxygenases (COX).”
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“Indeed, a subset of non-steroidal anti-inflammatory drugs also affects amyloid production, by reducing the secretion of Ab42 from cultured cells, independently of their effects on cyclooxygenase activity (Weggen et al., 2001; Sagi et al., 2003).”
Background
Defining Molecular Targets to Prevent Alzheimer Disease
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“Intriguingly, there is evidence that certain nonsteroidal anti-inflammatory drugs such as ibuprofen may subtly modulate -secretase cleavage to lower A 42 production without impairing A 40 production and Notch cleavage.(15) Derivatives of certain anti-inflammatory drugs that can no longer inhibit cyclooxygenase activit…”
Background
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“Only those interventions that also have at east some human track record are provided, since such examles are best suited to help put the question posed above in erspective or to shed light on this question in the foreseeable uture [6,12,14,30,31,49,66,78,80,86,87,109,110,116,117, 18,130,138,157–159, 170, 174, 181, 196…”
Background
Presenilin function and γ‐secretase activity
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“Importantly, these compounds do not inhibit APP-CTFc, Notch-NICD or ErbB4ICD production by c-secretase, suggesting that biochemical differences exist between the c-secretase cleavage that produces Ab versus that which produces ICD fragments (Weggen et al. 2001; 2003a).”
Background
Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma
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“NSAIDs act directly on the generation of Abeta (Weggen et al., 2001).”
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“prone A 42 peptide and increase a 38-residue form of A .(62) This pharmacological property is independent of”
Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease
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“There are several other mechanisms involved in the pathology of AD that bypass the COX-2 pathway, and it may be that the beneficial effect of non-selective NSAIDs reported previously could be the result of an action on such alternative mechanisms. For example, it has been demonstrated in cultured cells that ibuprofen,…”
Background
Making the final cut: Pathogenic amyloid-β peptide generation by γ-secretase
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“lindac sulfide (Weggen et al., 2001), a nitric oxide-releasing”
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“…of -secretase cleaving enzyme 1 (BACE 1), an effect mediated by the activation of PPAR (Sastre et al., 2006), modulation of -secretase activity (Weggen et al., 2001; Eriksen et al., 2003) and inhibition of signal transduction pathways involved in cytokine-mediated inflammation such as NF B and…”
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Selective inhibition of Aβ42 production by NSAID R‐enantiomers
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Overexpression of Monocyte Chemotactic Protein-1/CCL2 in β-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse β-Amyloid Deposition
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Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions
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“GSMs cause a decrease in A 42 and A 40, which is accompanied by an increase in shorter A peptides, such as A 37 and A 38 (9, 10, 23).”
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Cyclooxygenase-2 Promotes Amyloid Plaque Deposition in a Mouse Model of Alzheimer's Disease Neuropathology
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“Non-steroidal anti-inflammatory drugs like ibuprofen and indomethacin also modulate the -secretase cleavage of APP [111].”
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γ‐Secretase inhibitors and modulators for Alzheimer’s disease
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“These compounds are not only structurally distinct from the Ab42-lowering NSAIDs, but they also appear to work by a somewhat different mechanism and putatively through a different target within c-secretase.”
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Neuronal oxidative damage from activated innate immunity is EP2 receptor‐dependent
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“…the effects of indomethacin and ibuprofen in the experiments described above, including suppression of PGE2 production, suppres- sion of other COX products, and COX-independent actions of NSAIDs that include antioxidant activity (Hamburger and McCay 1990; Asanuma et al. 2001; Weggen et al. 2001).”
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Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models
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Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139
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“Select nonsteroidal anti-inflammatory drugs have been shown to increase A 1–38 while reducing A 1–42 in vitro (Weggen et al., 2001; Beher et al., 2005).”
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Alzheimer's disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products
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“Second, a subset of NSAIDs such as Ibu, sulindac sulfide (SSide), indomethacin (Ind) (Weggen et al., 2001) and flurbiprofen (Flu) (Eriksen et al., 2003) selectively decreased the secretion of Aß(1-42) from cultured cells independently of cyclooxygenase (COX) activity and lowered the amount of…”
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Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs Preserve Intramembrane Cleavage of the Amyloid Precursor Protein (APP) and ErbB-4 Receptor and Signaling through the APP Intracellular Domain
Weggen, S., Eriksen, J. L., Sagi, S. A., Pietrzik, C. U., Golde, T. E., & Koo, E. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304824200 · Cited by 126
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Treatment Strategies Targeting Amyloid -ProteinPreprint
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Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention
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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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