Nonsteroidal Anti-Inflammatory Drugs Can Lower Amyloidogenic Aß 42 by Inhibiting Rho
Abstract
A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.
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Aβ production by secretase-dependent cleavage of APP is enhanced by RhoA/ROCK activation.
“The opposite relation between Aβ and RhoA also exists, as Aβ production by the secretase-dependent cleavage of APP has been found enhanced by RhoA/ROCK activation [180].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [180]
The intake of ibuprofen and aspirin has been associated with a reduction in the risk of developing cancer, in particular colon cancer, and possibly Alzheimer's disease because of preferentially reduced secretion of the highly amyloidogenic Abeta42 peptide.
“The intake of ibuprofen and aspirin has also been associated with a reduction in the risk of developing cancer, in particular colon cancer, and possibly Alzheimer’s disease because of preferentially reduced secretion of the highly amyloidogenic, Abeta42 peptide (62,63).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [63]
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References 15 · Cited by 316
- Authors
- Zhou, Y., Su, Y., Li, B., Liu, F., Ryder, J. W., Wu, X., Gonzalez-DeWhitt, P. A., Gelfanova, V., Hale, J. E., May, P. C., Paul, S. M., & Ni, B.
- Affiliations
- Eli Lilly (United States) (US)
- Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
- Corresponding author
- Zhou, Yan
- Paul, Steven M.
- ORCID
- Venue
- Science
- Published
- 2003-11-14
- Volume
- 302
- Issue
- 5648
- Pages
- 1215-1217
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2107288853
- Cited by
- 316
- References
- 15
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 10 · 2021: 13 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 13 · 2016: 7 · 2015: 13 · 2014: 15 · 2013: 20 · 2012: 16
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- nonsteroidal anti-inflammatory drugs, amyloid-beta 42, Rho GTPases, Rho kinase, ROCK inhibition, Y-27632, APP processing, Alzheimer's disease, transgenic mouse model, drug repurposing
- MeSH terms
- Amides, Animals, Anti-Inflammatory Agents, Non-Steroidal, Brain, Enzyme Inhibitors, Guanosine Triphosphate, Humans, Ibuprofen, Mice, Transgenic, Peptide Fragments, Endopeptidases, Polyisoprenyl Phosphates, Pyridines, Sesquiterpenes, Sulindac, Transfection, Signal Transduction, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Protein Serine-Threonine Kinases, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Amyloid Precursor Protein Secretases, rho-Associated Kinases
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