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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
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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“Anti-inflammatory drugs such as NSAIDs have been used as a potential treatment in AD because of their capacity to bind to and stimulate the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ as well as their direct effects on the amyloid formation [101].”
From Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review (2020) · cites this paper as [101]
In the citing paper
“The first GSMs were discovered by recognizing that ibuprofen, indomethacin and sulindac reduce Abeta42 levels (Weggen et al., 2001) through modulation of gamma-secretase activity (Eriksen et al., 2003).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Weggen et al., 2001
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Cites
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
Cyclooxygenases: Structural, cellular, and molecular biology
Smith, W. L., DeWitt, D. L., & Garavito, R. M. (2000) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.69.1.145 · Cited by 2,925
A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., et al. (1999) · Nature · doi:10.1038/19083 · Cited by 2,100
McGeer, P. L., Schulzer, M., & McGeer, E. G. (1996) · Neurology · doi:10.1212/wnl.47.2.425 · Cited by 1,367
Risk of Alzheimer's disease and duration of NSAID use
Stewart, W. F., Kawas, C., Corrada, M., & Metter, E. J. (1997) · Neurology · doi:10.1212/wnl.48.3.626 · Cited by 1,132
Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00372.2001 · Cited by 1,053 · cited 1×
“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”
BackgroundClinical 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
Neurotoxicity of a Fragment of the Amyloid Precursor Associated with Alzheimer's Disease
Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., & Neve, R. L. (1989) · Science · doi:10.1126/science.2474201 · Cited by 907
McEvoy, G. K. (1994) · Oncology Issues · doi:10.1080/10463356.1994.11904493 · Cited by 888
Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease
Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W. K., Teter, B., Tran, T., Ubeda, O. J., Ashe, K. H., Frautschy, S. A., et al. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-15-05709.2000 · Cited by 876
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Broeck, B. V., Broeckhoven, C. V., & Kumar‐Singh, S. (2007) · Neurodegenerative Diseases · doi:10.1159/000105156 · Cited by 65
“caution is needed because the reduction of the amount of Aβ40 might mimic the effect of PS mutations and in this way worsen instead of ameliorate the phenotype. In this eventuality, strategies aimed at altering APP processing to cause a selective increase in Aβ40 could be useful.Some nonsteroidal anti-inflammatory dru…”
BackgroundPiperidine Acetic Acid Based γ-Secretase Modulators Directly Bind to Presenilin-1
Crump, C. J., Fish, B. A., Castro, S. V., Chau, D.-M., Gertsik, N., Ahn, K., Stiff, C. M., Pozdnyakov, N., Bales, K. R., Johnson, D. S., et al. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn200098p · Cited by 65
Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice
Xu, Z., Dong, Y., Wang, H., Culley, D. J., Marcantonio, E. R., Crosby, G. J., Tanzi, R. E., Zhang, Y., & Xie, Z. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096752 · Cited by 64
“matory drug (NSAID), which has been shown to attenuate neuroinflammation [18] and reduce Ab levels [19].”
Aβ42 Overproduction Associated with Structural Changes in the Catalytic Pore of γ-Secretase
Isoo, N., Sato, C., Miyashita, H., Shinohara, M., Takasugi, N., Morohashi, Y., Tsuji, S., Tomita, T., & Iwatsubo, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611549200 · Cited by 65
A comparison of oral midazolam and nitrous oxide sedation for dental extractions in children
Wilson, K. E., Girdler, N. M., & Welbury, R. R. (2006) · Anaesthesia · doi:10.1111/j.1365-2044.2006.04835.x · Cited by 67
Prostaglandins and Leukotrienes
McCracken, J. A. (2007) · Humana Press eBooks · doi:10.1007/978-1-59259-829-8_7 · Cited by 64
A Randomized, Double-blind, Placebo Controlled-trial of Triflusal in Mild Cognitive Impairment
Gómez‐Isla, T., Blesa, R., Boada, M., Clarimón, J., del Ser, T., Domènech, G., Ferro, J. M., Gómez‐Ansón, B., Manubens, J. M., Martínez‐Lage, J. M., et al. (2008) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181611024 · Cited by 65
Woodling, N. S., & Andreasson, K. I. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00016 · Cited by 62
Portelius, E., Broeck, B. V., Andréasson, U., Gustavsson, M. K., Mercken, M. H., Zetterberg, H., Borghys, H., & Blennow, K. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100573 · Cited by 62
“Based on previous results [14–16,21,22], 8 different isoforms were selected for further statistical analysis: Aβ1−15, Aβ1−16, Aβ1−34, Aβ1−37, Aβ1−38, Aβ1−39, Aβ1−40, and Aβ1−42.”
Review on anti-alzheimer drug development: approaches, challenges and perspectives
Abdallah, A. E. (2024) · RSC Advances · doi:10.1039/d3ra08333k · Cited by 63
Hashimoto, Y., Kaneko, Y., Tsukamoto, E., Frankowski, H., Kouyama, K., Kita, Y. A., Niikura, T., Aiso, S., Bredesen, D. E., Matsuoka, M., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02513.x · Cited by 63
“Some recent clinical trials have been directed at reduction of Ab production from APP by administering neutralizing anti-Ab antibody and c-secretase inbibitors, including non-steroid anti-inflammatory drugs (Weggen et al. 2001; Eriksen et al. 2003).”
BackgroundFluhrer, R., Steiner, H., & Haass, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r800040200 · Cited by 63
Presenilins in Memory, Alzheimer's Disease, and Therapy
Marjaux, E., Hartmann, D., & Strooper, B. D. (2004) · Neuron · doi:10.1016/s0896-6273(04)00218-1 · Cited by 63
Prostaglandin H2‐derived adducts of proteins correlate with Alzheimer's disease severity
Zagol-Ikapitte, I. A., Masterson, T. S., Amarnath, V., Montine, T. J., Andreasson, K. I., Boutaud, O. G., & Oates, J. A. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03264.x · Cited by 62
“In addition, the findings that some NSAIDs at high concentrations also exert COX-independent effects, including alteration of c-secretase cleavage of the amyloid-precursor protein (Weggen et al. 2001; Eriksen et al. 2003; Weggen et al. 2003), provide alternative hypotheses.”
BackgroundStrategies, Development, and Pitfalls of Therapeutic Options for Alzheimer's Disease
Haas, C. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110986 · Cited by 61
“Previous reports utilizing both cultured cells and mouse models have identified that certain non-steroidal anti-inflammatory drugs (NSAIDs) — ibuprofen, sulindac sulfide, indomethacin, naproxen, and fluriprofen — have the ability to lower levels of A and reduce amyloid accumulation in brain tissue, in a manner not dep…”
BackgroundGreco, A., Ajmone‐Cat, M. A., Nicolini, A., Sciulli, M. G., & Minghetti, L. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10543 · Cited by 62
“Besides their well-known inhibitory effects on cyclooxygenase (COX) activity (Vane, 1971), at least some NSAIDs were shown to suppress inflammatory gene expression (Pan and Hung, 2002) and to affect amyloid formation independent of COX inhibition (Weggen et al., 2001).”
BackgroundAnti-inflammatory therapy in Alzheimer?s disease: is hope still alive?
van Gool, W. A., Aisen, P. S. S., & Eikelenboom, P. (2003) · Journal of Neurology · doi:10.1007/s00415-003-1146-5 · Cited by 61
“This observation may be explained by in vitro and animal experimental studies showing that a subset of the classical NSAIDs (but not selective COX-2 inhibitors) lower the amyloidogenic Aβ production independently of COX activity [ 29 ].”
ResultFindeis, M. A., Schroeder, F. C., McKee, T. D., Yager, D., Fraering, P. C., Creaser, S. P., Austin, W., Clardy, J., Wang, R., Selkoe, D. J., et al. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3000857 · Cited by 61
Self-citationMunter, L. M., Botev, A., Richter, L., Hildebrand, P. W., Althoff, V., Weise, C., Kaden, D., & Multhaup, G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.088005 · Cited by 63
Payton, S. M., Cahill, C. M., Randall, J., Gullans, S. R., & Rogers, J. T. (2003) · Journal of Molecular Neuroscience · doi:10.1385/jmn:20:3:267 · Cited by 60
“This therapeutic activity was independent of ibuprofen acting as an inhibitor of cyclooxygenase (Weggen et al., 2001).”
BackgroundAnti-inflammatory drugs and Alzheimer's disease
Martyn, C. N. (2003) · BMJ · doi:10.1136/bmj.327.7411.353 · Cited by 61
“This β amyloid peptide is the principal component of extracellular amyloid plaques, which are a characteristic histological feature of Alzheimer's disease. Activated microglia and reactive astrocytes surround these plaques, and evidence of a local increase in pro-inflammatory mediators exists. Whether this inflammator…”
BackgroundNicolakakis, N. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00021 · Cited by 60
“Of note, NSAIDs were shown to be effective independently of action on their classical targets, the COX enzymes, as evidenced in COX-1 and COX-2-defi cient mouse embryonic fi broblasts (Weggen et al., 2001).”
Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase
Funamoto, S., Sasaki, T., Ishihara, S., Nobuhara, M., Nakano, M., Watanabe‐Takahashi, M., Saito, T., Kakuda, N., Miyasaka, T., Nishikawa, K., et al. (2013) · Nature Communications · doi:10.1038/ncomms3529 · Cited by 60
Mertens, J., Stüber, K., Wunderlich, P., Ladewig, J., Kesavan, J., Vandenberghe, R. R., Vandenbulcke, M., Damme, P. V., Walter, J., Brüstle, O., et al. (2013) · Stem Cell Reports · doi:10.1016/j.stemcr.2013.10.011 · Cited by 60
“…of nonsteroidal anti-inflammatory drugs (NSAIDs) were identified to act as g-secretase modulators (GSMs) that specifically lower the production of Ab42 in favor of shorter Ab isoforms by targeting g-secretase PS1 or its substrate APP (Jumpertz et al., 2012; Kukar et al., 2008; Weggen et al., 2001).”
InfluentialProtease inhibitors as potential disease-modifying therapeutics for Alzheimer’s disease
Beher, D., & Graham, S. L. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.11.1385 · Cited by 61
“This leads to an enhanced production of the shorter Aβ(1-38) peptide without affecting Aβ(1-40) production [172].”
BackgroundInfluentialStress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders
Kitamura, Y., & Nomura, Y. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00301-7 · Cited by 59
Turning the tide on Alzheimer’s disease: modulation of γ-secretase
Luo, J. E., & Li, Y.-M. (2022) · Cell & Bioscience · doi:10.1186/s13578-021-00738-7 · Cited by 59
Ren, Z., Schenk, D., Basi, G. S., & Shapiro, I. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702739200 · Cited by 59
Molecular mechanism of intramembrane proteolysis by γ-secretase
Tomita, T. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu049 · Cited by 58
Anti-inflammatory treatment in AD mice protects against neuronal pathology
Choi, J., Jenkins, B. G., Carreras, I., Kaymakçalan, Ş., Cormier, K., Kowall, N. W., & Dedeoglu, A. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.07.032 · Cited by 59
“Ibuprofen reduces the generation of Aβ1–42, the most toxic Aβ species, in addition to its well-known role as a cyclooxygenase (COX) inhibitor (Weggen et al., 2001).”
InfluentialHarris, J. R. (2002) · Micron · doi:10.1016/s0968-4328(02)00029-x · Cited by 59
Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients
Panza, F., Seripa, D., Solfrizzi, V., Imbimbo, B. P., Lozupone, M., Leo, A., Sardone, R., Gagliardi, G., Lofano, L., Creanza, B. C., et al. (2016) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2016.1241232 · Cited by 61
“Ibuprofen, a nonselective COX inhibitor, is part of a subset of NSAIDs that reduce Aβ1–42 levels by modulating the activity of the γ-secretase enzyme complex [46].”
BackgroundBansal, R., & Singh, R. (2017) · Medicinal Research Reviews · doi:10.1002/med.21458 · Cited by 62
Balducci, C., Mehdawy, B., Mare, L., Giuliani, A., Lorenzini, L., Sivilia, S., Giardino, L., Calzà, L., Lanzillotta, A., Sarnico, I., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101839 · Cited by 58
Bernardo, A., Ajmone‐Cat, M. A., Gasparini, L., Ongini, E., & Minghetti, L. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02932.x · Cited by 58
Altered γ‐secretase activity in mild cognitive impairment and Alzheimer's disease
Kakuda, N., Shoji, M., Arai, H., Furukawa, K., Ikeuchi, T., Akazawa, K., Takami, M., Hatsuta, H., Murayama, S., Hashimoto, Y., et al. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201200214 · Cited by 58
“…effect’ in the 3-([3-cholamidopropyl]dimetylammonio)-2-hydroxy-1- propanesulfonate (CHAPSO)-reconstituted g -secretase system (Takami et al, 2009; Weggen et al, 2001) in which the addition of sulindac sulfide to the g -secretase reaction mixture, as expected, significantly suppressed A b 42…”
Lost in Translation: Neuropsychiatric Drug Development
Becker, R. E., & Greig, N. H. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000446 · Cited by 56
“The rationale for this trial rested on unreplicated early data and suspect post hoc assumptions: An initial report from transgenic mice showing that tarenflurbil lowered Ab42 in brain by targeting g-secretase (43, 44) could not be confirmed by others (45).”
BackgroundMechanisms of neurodegeneration — Insights from familial Alzheimer’s disease
Chávez‐Gutiérrez, L., & Szaruga, M. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.03.005 · Cited by 59
γ-Secretase: a complex target for Alzheimer's disease
Lundkvist, J., & Näslund, J. (2006) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2006.10.002 · Cited by 58
CCR1 is an early and specific marker of Alzheimer's disease
Halks‐Miller, M., Schroeder, M. L., Haroutunian, V. H., Moenning, U., Rossi, M. R., Achim, C. L., Purohit, D. P., Mahmoudi, M., & Horuk, R. (2003) · Annals of Neurology · doi:10.1002/ana.10733 · Cited by 58
Lee, D. C., Rizer, J., Hunt, J. B., Selenica, M. ‐. B., Gordon, M. N., & Morgan, D. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12002 · Cited by 57
Broeck, B. V., Chen, J., Tréton, G., Desmidt, M., Hopf, C., Ramsden, N. G., Karran, E. H., Mercken, M. H., & Rowley, A. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01207.x · Cited by 59
“…the amyloidogenic function of g-secretase without interfering with the cleavage of other substrates like Notch (Weggen et al., 2001; 2003a) and they do not cause an accumulation of APP-CTF (Weggen et al., 2001; Gasparini et al., 2004) or interfere with the production of AICD (Weggen et al., 2003a).”
BackgroundInfluentialBlood‐based neurochemical diagnosis of vascular dementia: a pilot study
Bibl, M., Esselmann, H., Mollenhauer, B., Weniger, G., Welge, V., Liess, M., Lewczuk, P., Otto, M., Schulz, J. B., Trenkwalder, C., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04763.x · Cited by 57
“With regard to the importance of the peptide in drug discovery studies, the selectiveness of c-secretase inhibiting compounds (e.g., nonsteroidal anti-inflammatory drugs) may be estimated by the amount of Ab 1–38 or Ab1–40 relative to the reduction of Ab1–42 (Weggen et al. 2001).”
BackgroundSmall, G. W., Siddarth, P., Silverman, D. H. S., Ercoli, L. M., Miller, K. J., Lavretsky, H., Bookheimer, S. Y., Huang, S.-C., Barrio, J. R., & Phelps, M. E. (2008) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31818cd3a4 · Cited by 60
Alzheimer's disease therapeutic research: the path forward
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γ‐Secretase component presenilin is important for microglia β‐amyloid clearance
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Zaja‐Milatovic, S., Gupta, R. C., Aschner, M., Montine, T. J., & Milatović, D. (2008) · NeuroToxicology · doi:10.1016/j.neuro.2008.04.009 · Cited by 57
Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women
Kang, J. H., & Grodstein, F. (2003) · Neurology · doi:10.1212/01.wnl.0000065980.33594.b7 · Cited by 57
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Imbimbo, B. P. (2004) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.13.11.1469 · Cited by 54
“Transgenic mice overexpressing COX-2 show memory dysfunction, neuronal apoptosis and astrocytic activation in an age-dependent manner [22].”
BackgroundResultInfluentialHahn, S., Brüning, T., Ness, J., Czirr, E., Baches, S., Gijsen, H., Korth, C., Pietrzik, C. U., Bulic, B., & Weggen, S. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07118.x · Cited by 42
Self-citationHao, W., Liu, Y., Liu, S., Walter, S., Grimm, M. O. W., Kiliaan, A. J., Penke, B., Hartmann, T., Rübe, C. E., Menger, M. D., et al. (2010) · Brain · doi:10.1093/brain/awq325 · Cited by 54
“ing (Weggen et al., 2001; Eriksen et al., 2003).”
Backgroundγ-Secretase and the Intramembrane Proteolysis of Notch
Jorissen, E., & Strooper, B. D. (2010) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(10)92006-1 · Cited by 61
“A subset of nonsteroidal anti-inflammatory drugs, such as ibupro fen and sulindac sulfide, as well as enantiomers of flurbiprofen, were shown to change the profiles of the different Aβ species in cell cultures and mice in vivo, decreasing the relative amounts of aggregation-prone Aβ42, indepen dently of their abilit…”
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Veld, B. A. I. (2002) · Epidemiologic Reviews · doi:10.1093/epirev/mxf001 · Cited by 56
“Finally, there is recent evidence that a subcategory of NSAIDs suppresses the formation of amyloid-β42, possibly through a change in γ-secretase activity, while others do not (25).”
BackgroundKwok, J. B., Halliday, G. M., Brooks, W. S., Dolios, G., Laudon, H., Murayama, O., Hallupp, M., Badenhop, R. F., Vickers, J. C., Wang, R., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211827200 · Cited by 56
Self-citationNSAIDs: how they work and their prospects as therapeutics in Alzheimer's disease
Sastre, M. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00020 · Cited by 57
Mitterreiter, S., Page, R. M., Kamp, F., Hopson, J., Winkler, E., Ha, H., Hamid, R., Herms, J. W., Mayer, T. U., Nelson, D. J., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1199-10.2010 · Cited by 55
Contemporary dental photography: selection and application.
Terry, D. A., Snow, S. R., & McLaren, E. A. (2008) · PubMed · Cited by 57
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Hollas, M. A. R., Aissa, M. B., Lee, S., Gordon-Blake, J. M., & Thatcher, G. R. J. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.10.006 · Cited by 55
Czirr, E., Leuchtenberger, S., Dorner‐Ciossek, C., Schneider, A., Jucker, M., Koo, E. H., Pietrzik, C. U., Baumann, K., & Weggen, S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700618200 · Cited by 54
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Basi, G. S., Hemphill, S. S., Brigham, E. F., Liao, A., Aubele, D. L., Baker, J., Barbour, R., Bova, M. P., Chen, X., Dappen, M. S., et al. (2010) · Alzheimer s Research & Therapy · doi:10.1186/alzrt60 · Cited by 53
Mammary Development and Breast Cancer: The Role of Stem Cells
Ercan, C., van Diest, P. J., & Vooijs, M. (2011) · Current Molecular Medicine · doi:10.2174/156652411795678007 · Cited by 55
“Since γ-secretase has many different substrates, pleiotropic effects are unavoidable when targeting this enzyme, although modulators have been identified that may show selectivity for specific substrates [155].”
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Li, X., Wang, Z., Tan, L., Wang, Y., Lu, C., Chen, R., Zhang, S., Gao, Y., Liu, Y., Yin, Y., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2016.10.010 · Cited by 53
Coxibs and Alzheimer's disease: Should they stay or should they go?
Firuzi, O., & Praticò, D. (2006) · Annals of Neurology · doi:10.1002/ana.20774 · Cited by 54
“It has been recently postulated that the beneficiary effect of selective NSAIDs is through other mechanisms rather than their antiinflammatory properties.(28,29)”
BackgroundMutations in amyloid precursor protein affect its interactions with presenilin/γ-secretase
Herl, L. D., Thomas, A. V., Lill, C. M., Banks, M., Deng, A., Jones, P., Spoelgen, R., Hyman, B. T., & Berezovska, O. (2009) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2009.02.008 · Cited by 59
“A subset of Aβ42-lowering non-steroidal anti-inflammatory drugs (Weggen et al., 2001) had an opposite effect on PS1 conformation (“opening”) (Lleo et al.”
BackgroundLee, E. O., Shin, Y. J., & Chong, Y. H. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.05.012 · Cited by 54
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Xia, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.02.011 · Cited by 54
Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer’s Disease
Martins, M., Silva, R. V. D. S., Pinto, M. M. M., & Sousa, E. (2020) · Pharmaceuticals · doi:10.3390/ph13090242 · Cited by 56
Amanullah, A., Upadhyay, A., Dhiman, R., Singh, S., Kumar, A., Ahirwar, D. K., Gutti, R. K., & Mishra, A. (2022) · Cancers · doi:10.3390/cancers14184385 · Cited by 53
Electrochemiluminescence in Bioanalysis
Rhyne, P., Wong, O. T., Zhang, Y. J., & WEINER, R. S. (2009) · Bioanalysis · doi:10.4155/bio.09.80 · Cited by 55
Sun, Z. J., Asberom, T., Bara, T. A., Bennett, C. E., Burnett, D. A., Chu, I., Clader, J. W., Cohen-Williams, M. E., Cole, D., Czarniecki, M., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201407j · Cited by 53
A perspective review on role of novel NSAID prodrugs in the management of acute inflammation
Peesa, J. P., Yalavarthi, P. R., Rasheed, A., & Mandava, V. B. R. (2016) · Journal of Acute Disease · doi:10.1016/j.joad.2016.08.002 · Cited by 53
“Flurbiprofen inhibits both COX enzymes effectively([59]).”
Zhang, W., Bai, M., Ye, X., Hao, J., Zhang, Z., Su, C., Lei, G., Miao, J., & Li, Z. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.12.023 · Cited by 53
RetractedLeitch, J., Anderson, K., Gambhir, S., Millar, K., Robb, N. D., McHugh, S., & Kenny, G. N. C. (2004) · Anaesthesia · doi:10.1111/j.1365-2044.2004.03761.x · Cited by 53
Carlo, M. D. (2009) · European Biophysics Journal · doi:10.1007/s00249-009-0439-8 · Cited by 56
Microglia in Neurodegenerative Disorders
Tejera, D., & Heneka, M. T. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9658-2_5 · Cited by 54
The same γ‐secretase accounts for the multiple intramembrane cleavages of APP
Zhao, G., Tan, J., Mao, G., Cui, M., & Xu, X. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04302.x · Cited by 52
“1, lanes 18 and 19) when cells were cultured in the presence of these inhibitors at concentrations at which both ibuprofen and sulindac sulfide have been shown to alter the formation of Ab42 and Ab38 (Weggen et al. 2001).”
BackgroundNSAIDs for the Chemoprevention of Alzheimer’s Disease
Szekely, C. A., Town, T., & Zandi, P. P. (2007) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/1-4020-5688-5_11 · Cited by 53
“[9–11] This novel property of NSAIDs is currently being explored in epidemiologic studies.”
BackgroundTacrine-Based Hybrids: Past, Present, and Future
Bubley, A., Erofeev, A. S., Gorelkin, P. V., Beloglazkina, E. K., Majouga, A. G., & Krasnovskaya, O. O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021717 · Cited by 52
Piperidine-derived γ-secretase modulators
Hall, A., Elliott, R. L., Giblin, G. M. P., Hussain, I., Musgrave, J., Naylor, A., Sasse, R. Z., & Smith, B. B. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.08.072 · Cited by 51
Cunningham, C. M., & Skelly, D. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9312-5 · Cited by 51
“selective COX-1 and COX-2 inhibitors SC-560 or celecoxib, lower Aβ1-42 independently of their impact on COX activity (Weggen et al. 2001).”
BackgroundPettersson, M., Stepan, A. F., Kauffman, G. W., & Johnson, D. S. (2013) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2013.821465 · Cited by 51
“Modulating g-secretase activity without impacting Notch processing emerged as a potential disease-modifying treatment strategy for AD when certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to selectively reduce the formation of pathogenic Ab42 species without inhibiting the physiological function of g-…”
BackgroundPlants traditionally used in age-related brain disorders (dementia): an ethanopharmacological survey
Suganthy, N., Pandian, S. K., & Kasi, P. D. (2013) · Pharmaceutical Biology · doi:10.3109/13880209.2012.738423 · Cited by 53
Concepts for the treatment of Alzheimer's disease: molecular mechanisms and clinical application
Pietrzik, C. U., & Behl, C. (2005) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2005.00435.x · Cited by 52
“This intervention appeared to be specific for APP processing and did not affect other signalling pathways, such as Notch signalling (Weggen et al. 2001).”
BackgroundSelf-citationIbuprofen for Alzheimer's disease
Tabet, N., & Feldman, H. (2003) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004031 · Cited by 51
Ibuprofen and Lipoic Acid Diamides as Potential Codrugs with Neuroprotective Activity
Sozio, P., D'Aurizio, E., Iannitelli, A., Cataldi, A., Zara, S., Cantalamessa, F., Nasuti, C., & Di Stefano, A. (2010) · Archiv der Pharmazie · doi:10.1002/ardp.200900152 · Cited by 51
Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease
D’Onofrio, G., Panza, F., Frisardi, V., Solfrizzi, V., Imbimbo, B. P., Paroni, G., Cascavilla, L., Seripa, D., & Pilotto, A. (2011) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.645534 · Cited by 52
“NSAIDs shift the cleavage of APP to promote shorter Ab species, in particular Ab1 -- 38, but do not inhibit the cleavage of other g-secretase substrates [34,37,38].”
BackgroundInfluentialHong, Z., Shi, X., Zhu, K., Wu, T., & Zhu, Y. Z. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0147-x · Cited by 50
“Extensive literatures have documented that IBU, one of the most commonly used NSAIDs, could significantly inhibit activation of human primary microglia or THP-1 macrophages [28] and suppress brain inflammation [5,29-31].”
BackgroundBrendel, M., Jaworska, A. M., Herms, J. W., Trambauer, J., Rötzer, C., Gildehaus, F.-J., Carlsen, J., Cumming, P. D., Bylund, J., Luebbers, T., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.74 · Cited by 49
Ching, T., Chiang, W., Chen, C., & Hsu, A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00688.x · Cited by 51
“Recent studies have reported that a subset of NSAIDs can lower the production of amyloidigenic Ab42 or Ab40 peptides, potentially independent of its COX inhibitory activity (Weggen et al., 2001; Gasparini et al., 2004).”
BackgroundWagner, S. L., Zhang, C. M., Cheng, S., Nguyen, P. A. H., Zhang, X., Rynearson, K. D., Wang, R., Li, Y., Sisodia, S. S., Mobley, W. C., et al. (2014) · Biochemistry · doi:10.1021/bi401537v · Cited by 50
Self-citationThe Anti-inflammatory Drug Indomethacin Alters Nanoclustering in Synthetic and Cell Plasma Membranes
Zhou, Y., Plowman, S. J., Lichtenberger, L. M., & Hancock, J. F. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.141200 · Cited by 50
Prade, E., Barucker, C., Sarkar, R., Althoff-Ospelt, G., del Amo, J. M. L., Hossain, S., Zhong, Y., Multhaup, G., & Reif, B. (2016) · Biochemistry · doi:10.1021/acs.biochem.5b01272 · Cited by 50
Developing Preventive Therapies for Chronic Diseases: Lessons Learned from Alzheimer's Disease
Selkoe, D. J. (2008) · Nutrition Reviews · doi:10.1111/j.1753-4887.2007.tb00370.x · Cited by 50
Alberghina, L., & Colangelo, A. M. (2006) · BMC Neuroscience · doi:10.1186/1471-2202-7-s1-s2 · Cited by 51
The molecular basis for inhibition of sulindac and its metabolites towards human aldose reductase
Zheng, X., Zhang, L., Zhai, J. H., Chen, Y., Luo, H., & Hu, X. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.11.023 · Cited by 49
“For example, SLD sulfide potentially modulates c-secretase function and directly inhibits 5-lipoxygenase, whereas neither SLD nor SLD sulfone interacts with those enzymes [19–22].”
BackgroundKretner, B., Fukumori, A., Gutsmiedl, A., Page, R. M., Luebbers, T., Galley, G., Baumann, K., Haass, C., & Steiner, H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213587 · Cited by 49
Panza, F., Solfrizzi, V., Frisardi, V., Imbimbo, B. P., Capurso, C. A., D’Introno, A., Colacicco, A. M., Seripa, D., Vendemiale, G., Capurso, A., et al. (2009) · Aging Clinical and Experimental Research · doi:10.1007/bf03327445 · Cited by 49
Zhao, B., Liu, Y., Gao, X., Zhai, H., Guo, J., & Wang, X. (2014) · Molecules · doi:10.3390/molecules191016925 · Cited by 49
“[7] found that long-term treatment with non-steroidal anti-inflammatory drugs reduced the risk of AD and delayed the progression of AD.”
BackgroundSubstrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
Uemura, K., Farner, K. C., Hashimoto, T., Nasser‐Ghodsi, N., Wolfe, M. S., Koo, E. H., Hyman, B. T., & Berezovska, O. (2010) · Nature Communications · doi:10.1038/ncomms1129 · Cited by 49
“Treatment with aspirin or naproxen, non-steroidal anti-inflammatory drugs (NSAIDs) that do not affect the Aβ 42/40 rati”
BackgroundSelf-citation
Metadata
- 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
- Venue
- Nature
- Published
- 2001-11
- Volume
- 414
- Issue
- 6860
- Pages
- 212-216
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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