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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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“However, Notch cleavage was not found to be blocke”
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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].”
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“The epidemiological observation that prolonged usage of non-steroidal anti-inflammatory drugs such as ibuprofen offers partial protection against the development of AD could be explained by an anti-inflammatory effect, but such drugs have also been shown to function as direct modulators of γ-secretase that selectively…”
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Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 829
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MethodAPP mouse models for Alzheimer’s disease preclinical studies.
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“Further work into the potential of tackling c -secretase in a safe manner is based on overexpressing mice (Weggen et al , 2001) and novel insights into more safe approaches continue (De Strooper, 2014), illustrating the utility of the overexpression paradigm for certain types of preclinical studies…”
Microglia and neurodegeneration: The role of systemic inflammation
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“While it is known that some NSAIDs can lower Ab aggregation independent of their anti-inflammatory activity (Weggen et al., 2001), it has also been shown, in a large group of pooled prospective studies, that ‘‘amyloid-lowering’’ NSAIDs are not more effective in reducing the risk of AD than nonamyloid-lowering NSAIDs (…”
ResultProtein aggregation diseases: pathogenicity and therapeutic perspectives
Aguzzi, A., & O’Connor, T. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3050 · Cited by 766
“Drugs that modulate γ-secretase activity in this manner include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofe”
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Bossy-Wetzel, E., Schwarzenbacher, R., & Lipton, S. A. (2004) · Nature Medicine · doi:10.1038/nm1067 · Cited by 740
The role of inflammation in Alzheimer’s disease
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“The role of inflammatory processes in AD is supported by the use of non-steroidal anti-inflammatory drugs (NSAIDs) to reduce the Aβ levels (Weggen et al., 2001), and the risk of AD (Etminan et al., 2003).”
BackgroundThe secretases: enzymes with therapeutic potential in Alzheimer disease
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Self-citationKitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2868-05.2005 · Cited by 697
“On the other hand, epidemiological evidence suggests that use of a subset of nonsteroidal anti-inflammatory drugs can reduce the risk for AD, presumably by lessening the inflammatory component (Stewart et al., 1997; Anthony et al., 2000; Broe et al., 2000; Lim et al., 2000; Weggen et al., 2001; Zhou et al., 2003).”
BackgroundA century-old debate on protein aggregation and neurodegeneration enters the clinic
Lansbury, P. T., & Lashuel, H. A. (2006) · Nature · doi:10.1038/nature05290 · Cited by 691
Cytokines and cognition–the case for a head-to-toe inflammatory paradigm.
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NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18162 · Cited by 634
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MethodInfluentialCyclooxygenases: new forms, new inhibitors, and lessons from the clinic
Warner, T. D., & Mitchell, J. A. (2004) · The FASEB Journal · doi:10.1096/fj.03-0645rev · Cited by 617
Rho kinase, a promising drug target for neurological disorders
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“and an explanation for these data was provided with the observation that a subset of NSAIDs (ibuprofen, sulindac sulphide and indomethacin) reduced Aβ42 levels, independent of their effects on cyclooxygenase (COX) activit”
BackgroundInflammatory processes in Alzheimer's disease
Heneka, M. T., & O'Banion, M. K. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.017 · Cited by 782
“It has been shown that astrocytes throughout the entorhinal cortex of AD patients gradually accumulate Aβ1–42 positive material, and the amount of this material correlates positively with the extent of local AD pathology.”
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“The only comparable data on acute effects of anti-inflammatory drugs on Ab levels in transgenic mice are those of Weggen et al. (Weggen et al., 2001; Eriksen et al., 2003).”
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Self-citationNeuropathologic changes in Alzheimer's disease.
Wenk, G. L. (2003) · PubMed · Cited by 549
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“Finally, additional options for anti-AD drugs remain, such as the nonsteroidal anti-inflammatory drugs (Weggen et al, 2001), and compounds aimed to prevent toxicity of Ab and tau.”
BackgroundE PIDEMIOLOGY OF N EURODEGENERATION
Mayeux, R. P. (2003) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.26.043002.094919 · Cited by 531
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“The above results suggest that the tetrapeptide-release step from A 42 to A 38 would be a specific target of A 42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) (Weggen et al., 2001; Eriksen et al., 2003) and other A 42-enhancing compounds (Kukar et al., 2005).”
BackgroundThe mechanism of γ‐Secretase dysfunction in familial Alzheimer disease
Chávez‐Gutiérrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.79 · Cited by 495
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“Even in mice, NSAIDs directly affect the development of amyloid in the brain, reducing Aβ-42 peptide levels (Weggen et al., 2001).”
BackgroundMicroglia and Astrocytes in Alzheimer's Disease: Implications for Therapy
Fakhoury, M. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170720095240 · Cited by 499
“The view that NSAIDs delay some forms of AD pathology is also supported by in-vitro studies showing that these antiinflammatory drugs selectively prevent the accumulation of Aβ peptides in culture cells, likely through a decrease in APP production or metabolism [131, 132].”
ResultKoenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477
“…et al., 1998; Combs et al., 2000) and to act on neurons to alter the specificity of amyloid precursor protein processing by directly effecting -secretase specificity, although the effects are only observed at high drug concentrations (Weggen et al., 2001; Sagi et al., 2003; Kukar et al., 2005).”
BackgroundA Hundred Years of Alzheimer's Disease Research
Hardy, J. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.016 · Cited by 467
Presenilins and -Secretase: Structure, Function, and Role in Alzheimer DiseasePreprint
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“These g-secretase modulators are exemplified by a subset of nonsteroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and sulindac sulfide) that were the first compounds discovered to alter the g-secretase processing of APP in this therapeutically important manner (Weggen et al. 2001).”
BackgroundThe amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy
McGeer, P. L., & McGeer, E. G. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1177-7 · Cited by 467
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“A subset of NSAIDs preferentially decreased production of the highly amyloidogenic A 42 peptide from a variety of cultured cells, independently of cyclooxygenase activity (Weggen et al., 2001).”
BackgroundNeuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433
“(2) Effect on amyloid precursor protein (APP processing: The protective effect of NSAIDs has been associated with decreased secretion of Ab peptides and soluble APP, although there is still debate about the molecular mechanism involved (Weggen et al. 2001; Sastre et al. 2003).”
BackgroundInfluentialChen, C.-H., Zhou, W., Liu, S., Deng, Y., Cai, F., Tone, M., Tone, Y., Tong, Y., & Song, W. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000149 · Cited by 433
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“However, Notch cleavage (corresponding to the 49 position of Aβ) was not blocke”
BackgroundThe impact of systemic infection on the progression of neurodegenerative disease
Perry, V. H., Newman, T. A., & Cunningham, C. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1032 · Cited by 428
“In addition, this simple interpretation of the role of NSAIDs might have to be carefully reconsidered because some NSAIDs significantly reduce the secretion of amyloid-β (Aβ) by neuron”
BackgroundContribution of inflammatory processes to Alzheimer's disease: molecular mechanisms
Sastre, M., Klockgether, T., & Heneka, M. T. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2005.11.014 · Cited by 426
“However, the effect of NSAIDs on Ab generation has been proven to be independent of COX activity (Weggen et al., 2001), corroborating the recent failure of a clinical trial with a selective COX-2 inhibitor (Aisen et al., 2003) and suggesting another mechanism behind the protective effect of NSAIDs.”
BackgroundResultInfluentialNEURODEGENERATIVE DISEASES: New Concepts of Pathogenesis and Their Therapeutic Implications
Skovronsky, D., Lee, V. M. ‐., & Trojanowski, J. Q. (2006) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.1.110304.100113 · Cited by 432
NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
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Neuroinflammation in Alzheimer's disease and prion disease
Eikelenboom, P., Bate, C., van Gool, W. A., Hoozemans, J. J. M., Rozemüller, A. J. M., Veerhuis, R., & Williams, A. (2002) · Glia · doi:10.1002/glia.10146 · Cited by 412
“…for the classical NSAIDs that are known to inhibit both COX-1 and COX-2 but which have other, non-COX-mediated, modes of action, such as activation of nuclear receptor peroxisome proliferator-activated receptor- (PPAR ) and lowering A 42 production (Landreth et al., 2001; Weggen et al., 2001).”
BackgroundInsulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert, M., Brazil, D. P., Burks, D. J., Kushner, J. A., Ye, J., Flint, C. L., Farhang-Fallah, J., Dikkes, P., Warot, X. M., Rio, C., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07084.2003 · Cited by 488
“…-peptide that promotes inflammation and the intracellular accumulation of neurofibrillary tangles composed of paired helical filaments assembled from hyperphosphorylated forms of the microtubule-associated protein tau (Lucas et al., 2001; Selkoe, 2001; Weggen et al., 2001; Hardy and Selkoe, 2002).”
BackgroundThe two faces of protein misfolding: gain‐ and loss‐of‐function in neurodegenerative diseases
Winklhofer, K. F., Tatzelt, J., & Haass, C. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601930 · Cited by 410
“Familial AD (FAD)-associated muta- tions shift the cleavage from position 40 to position 42 of the Ab domain to produce a more aggregation prone Ab species (Ab42) or at least increase the ratio of Ab42/Ab40 (Haass and Selkoe, 2007).”
BackgroundInfluentialInhibition of amyloid-β aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761
Luo, Y., Smith, J. V., Paramasivam, V., Burdick, A. J., Curry, K. J., Buford, J. P., Khan, I. A., Netzer, W. J., Xu, H., & Butko, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182425199 · Cited by 408
Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T. C., Wang, R., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1575-04.2005 · Cited by 391
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“A 38 has been shown previously to be a major A species in brain and CSF, as well (Weggen et al., 2001; Wiltfang et al., 2002; Pype et al., 2003).”
BackgroundThe role of cerebral amyloid accumulation in common forms of Alzheimer disease
Gandy, S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25100 · Cited by 407
“Aβ42 is inhibited while an otherwise trace species, Aβ38, is generated (60).”
BackgroundReines, S. A., Block, G. A., Morris, J. C., Liu, G., Nessly, M. L., Lines, C. R., Norman, B., & Baranak, C. C. (2004) · Neurology · doi:10.1212/wnl.62.1.66 · Cited by 384
Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies
Selkoe, D. J. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-140-8-200404200-00047 · Cited by 208
“However, exciting studies in cultured cells and -amyloid precursor protein transgenic mice suggest that some NSAIDs associated with protection from Alzheimer disease (such as ibuprofen) can actually modulate -secretase processing of -amyloid precursor protein to decrease -amyloid protein 42 production without lowering…”
BackgroundYan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A. L., Citron, M., & Landreth, G. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-20-07504.2003 · Cited by 469
“A number of NSAIDs, including ibuprofen, have recently been reported to selectively regulate the processing of APP, and it has been argued that this effect may underlie their beneficial effects in AD (Weggen et al., 2001).”
BackgroundResultInfluentialMicroglia and inflammatory mechanisms in the clearance of amyloid β peptide
Rogers, J., Strohmeyer, R., Kovelowski, C. J., & Li, R. (2002) · Glia · doi:10.1002/glia.10153 · Cited by 381
“Alternatively, certain NSAIDs may either decrease A formation or promote A clearance, or both (Lee and Wurtman, 2000; Lim et al., 2000; Blasko et al., 2001; Weggen et al., 2001).”
BackgroundThe Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind
Ricciarelli, R., & Fedele, E. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170116143743 · Cited by 380
“Although the exact mechanism of action still remains unclear, these modulators are able to decrease the production of Aβ42 without reducing overall Aβ levels, do not increase APP CTFs and do not alter Notch processing [108].”
BackgroundBlasko, I., Stampfer‐Kountchev, M., Robatscher, P., Veerhuis, R., Eikelenboom, P., & Grubeck‐Loebenstein, B. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00101.x · Cited by 374
“Ibuprofen, flurbiprofen, indometacine and sulindac sulphide are, however, able to decrease Aβ42 production by influencing γ-secretase cleavage without affecting COX activity (Weggen et al., 2001; Eriksen et al., 2003).”
BackgroundPresenilin: Running with Scissors in the Membrane
Selkoe, D. J., & Wolfe, M. S. (2007) · Cell · doi:10.1016/j.cell.2007.10.012 · Cited by 379
“Such “modulators” of γ-secretase include certain nonsteroidal antiinflammatory drugs (NSAIDs) that apparently shift cleavage specificity from Aβ42 by one turn down the transmembrane helix to Aβ38 (Weggen et al., 2001).”
BackgroundSastre, M., Dewachter, I., Rossner, S., Bogdanovic, N., Rosen, E., Borghgraef, P., Evert, B. O., Dumitrescu-Ozimek, L., Thal, D. R., Landreth, G., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503839103 · Cited by 373
Levites, Y., Amit, T., Mandel, S. A., & Youdim, M. B. H. (2003) · The FASEB Journal · doi:10.1096/fj.02-0881fje · Cited by 372
“Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have beneficial effects in AD (63).”
BackgroundThe amyloid cascade hypothesis: are we poised for success or failure?
Karran, E., & De Strooper, B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13632 · Cited by 402
Qing, H., He, G., Ly, P. T. T., Fox, C. J., Staufenbiel, M., Cai, F., Zhang, Z., Wei, S., Sun, X., Chen, C.-H., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081588 · Cited by 373
Therapeutic approaches to Alzheimer's disease
Klafki, H., Staufenbiel, M., Kornhuber, J., & Wiltfang, J. (2006) · Brain · doi:10.1093/brain/awl280 · Cited by 362
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354
“Given that select NSAIDs can modulate Ab production , inhibit Ab aggregation, and affect other cell signaling pathways , it is possible that any potential protective effect of these NSAIDs could be due to target engagement other than cyclooxygenase (Lim et al., 2000; Weggen et al., 2001).”
Self-citationAβ40 Inhibits Amyloid Deposition In Vivo
Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T., & McGowan, E. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4849-06.2007 · Cited by 359
“Our data support the strategy that selectively targeting A 42 by allosterically modulating -secretase may be preferential to nonselective inhibition of -secretase activity (Weggen et al., 2001; Eriksen et al., 2003; Lleo et al., 2004).”
MethodSelf-citationSastre, M., Dewachter, I., Landreth, G. E., Willson, T. M., Klockgether, T., LEUVEN, F. V., & Heneka, M. T. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-30-09796.2003 · Cited by 361
“…between treatment with cytokines alone and with experiments in cell culture in which ibuprofen could decrease secretion of amyloid peptides, although these findings are contradictory and heavily debated (Blasko et al., 2001, Weggen et al., 2001; Avramovich et al., 2002; Takasashi et al., 2003).”
BackgroundResultNaproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group (2007) · Neurology · doi:10.1212/01.wnl.0000260269.93245.d2 · Cited by 354
Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease
Ferreira, S. T., Clarke, J. R., Bomfim, T. R., & Felice, F. G. D. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.12.010 · Cited by 363
“Interestingly, certain NSAIDs, such as ibuprofen, indomethacin, and sulindac sulfide, were shown to decrease Ab42 production by up to 80% in cultured cells, apparently via a COX-independent mechanism [105].”
Neuroinflammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer's Disease
Rojo, L. E., Fernández, J. A., Maccioni, A. A., Jimenez, J. M., & Maccioni, R. B. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2007.10.001 · Cited by 351
“This potential effect of NSAIDs on AD pathogenesis seems not to be mediated only by inhibition of COX activity (126).”
BackgroundCai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.856376 · Cited by 351
“Nevertheless, some specific nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and indomethacin were identified to directly affect Ab deposition by altering g-secretase activity rather than COX activity (77).”
BackgroundThe Endocannabinoid System: Drug Targets, Lead Compounds, and Potential Therapeutic Applications
Lambert, D. M., & Fowler, C. J. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058183t · Cited by 354
Immunology and immunotherapy of Alzheimer's disease
Weiner, H. L., & Frenkel, D. (2006) · Nature Reviews Immunology · doi:10.1038/nri1843 · Cited by 335
“However, a subset of NSAIDs lower amyloid-β 1–42 levels independently of COX enzyme activit”
BackgroundExtended results of the Alzheimer's disease anti‐inflammatory prevention trial
Breitner, J. C. S., Baker, L. D., Montine, T. J., Meinert, C. L., Lyketsos, C. G., Ashe, K. H., Brandt, J., Craft, S., Evans, D. A., Green, R. C., et al. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.12.014 · Cited by 327
“We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Ab1-42.”
BackgroundInfluentialAlzheimer's Disease and Mild Cognitive Impairment
Kelley, B. J., & Petersen, R. C. (2007) · Neurologic Clinics · doi:10.1016/j.ncl.2007.03.008 · Cited by 335
β-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease
Sun, X., Chen, W., & Wang, Y. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00221 · Cited by 340
“…immune system by activating microglia through some immunological receptors such as Toll-like Receptors 2 (TLR2), TLR4, TLR6, their coreceptors CD14, CD36, and CD47, which can probably destroy functional neurons by direct phagocytosis (Weggen et al., 2001; Neniskyte et al., 2011; Liu et al., 2012).”
BackgroundInflammation and Alzheimer’s disease
Lee, Y.-J., Han, S. B., Nam, S.-Y., Oh, K.-W., & Hong, J. T. (2010) · Archives of Pharmacal Research · doi:10.1007/s12272-010-1006-7 · Cited by 396
The role of amyloid β peptide 42 in Alzheimer's disease
Findeis, M. A. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.06.006 · Cited by 337
Abdul, H. M., Sama, M. A., Furman, J. L., Mathis, D. M., Beckett, T. L., Weidner, A. M., Patel, E., Baig, I., Murphy, M. P., LeVine, H., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1064-09.2009 · Cited by 324
“Suppression of glial activation may also dampen the abnormal production and/or processing of Aβ (Blasko et al., 2001; Weggen et al., 2001; Morihara et al., 2002; Yan et al., 2003).”
BackgroundSelf-citationNovel anti-inflammatory therapy for Parkinson's disease
Gao, H., Liu, B., Zhang, W., & Hong, J. (2003) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(03)00176-7 · Cited by 325
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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