The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Open accessAbstract
Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 Eriksen et al., 2003
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Glutamate neurotoxicity and diseases of the nervous system
Choi, D. W. (1988) · Neuron · doi:10.1016/0896-6273(88)90162-6 · Cited by 8,188
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599
Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516
Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., & Selkoe, D. J. (1999) · Nature · doi:10.1038/19077 · Cited by 1,959
Statins and the risk of dementia
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. S., & Drachman, D. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03155-x · Cited by 1,764
Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1
Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.-M., Pérez‐Tur, J., Hutton, M., Buée, L., Harigaya, Y., Yager, D., et al. (1996) · Nature · doi:10.1038/383710a0 · Cited by 1,486
Research works printed but not linked: 3
- Wechter, 2000, Cancer Res., 60, 2203
- Edbauer, 2003, Nat. Cell Biol., 7, 7
- Murray, 2000, Clin. Pharmacol. Ther., 67, 103
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284
Metadata
- Authors
- 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., & Golde, T. E.
- Affiliations
- Mayo Clinic (US)
- University of California San Diego (US)
- Corresponding author
- Golde, Todd E.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-08-01
- Volume
- 112
- Issue
- 3
- Pages
- 440-449
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC166298
- OpenAlex
- W2103071556
- Cited by
- 634
- References
- 52
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 11 · 2023: 11 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 15 · 2018: 11 · 2017: 18 · 2016: 25 · 2015: 18 · 2014: 31 · 2013: 32 · 2012: 37
- FWCI
- 23.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institutes of Health
- National Institute on Aging (P01AG020206, T32AG000216)
- National Institute of Neurological Disorders and Stroke (R01NS039072)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- nonsteroidal anti-inflammatory drugs, gamma-secretase, amyloid-beta 42, Alzheimer's disease, APP transgenic mice, ibuprofen, meclofenamic acid, dapsone, cyclooxygenase inhibition, drug repurposing
- MeSH terms
- Alzheimer Disease, Animals, Anti-Inflammatory Agents, Non-Steroidal, Brain, Cell Line, Female, Flurbiprofen, Humans, Meclofenamic Acid, Mice, Transgenic, Peptide Fragments, Endopeptidases, Protease Inhibitors, Stereoisomerism, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Amyloid Precursor Protein Secretases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
