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.

doi:10.1038/35102591

Cited by 1,388Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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. +6 more·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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Anti-inflammatory drugs such as NSAIDs have been used as a potential treatment in Alzheimer's disease because of their capacity to bind to and stimulate PPAR-γ as well as their direct effects on amyloid formation.
“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]
The first gamma-secretase modulators were discovered by recognizing that ibuprofen, indomethacin, and sulindac reduce Aβ42 levels through modulation of gamma-secretase activity.
“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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New mechanism proposed for NSAID reduction of Alzheimer's disease incidence
Bradbury, J. (2001) · The Lancet · doi:10.1016/s0140-6736(01)06696-x

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: Health Sciences › Medicine › Physiology › 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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