The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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
Citations
Cites
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A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
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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”
BackgroundClinical trial of indomethacin in Alzheimer's disease
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Neurotoxicity of a Fragment of the Amyloid Precursor Associated with Alzheimer's Disease
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Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease
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The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology
Funk, C. D. (2001) · Science · doi:10.1126/science.294.5548.1871 · Cited by 3,817
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
“The first GSMs were discovered by recognizing that ibuprofen, indomethacin and sulindac reduce Abeta42 levels (Weggen et al., 2001) through modulation of gammasecretase activity (Eriksen et al.”
The NALP3 inflammasome is involved in the innate immune response to amyloid-β
Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., & Golenbock, D. T. (2008) · Nature Immunology · doi:10.1038/ni.1636 · Cited by 2,441
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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