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Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of
Sascha Weggen1, Jason L Eriksen, Sarah A Sagi
1Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA.
The Journal of Biological Chemistry
|June 14, 2003
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce amyloid-beta 42 (A beta 42) peptide production by directly modulating gamma-secretase activity. This mechanism, independent of cyclooxygenase inhibition, offers new insights into Alzheimer's disease prevention strategies.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic nonsteroidal anti-inflammatory drug (NSAID) use is linked to reduced Alzheimer's disease (AD) risk.
- Some NSAIDs inhibit amyloidogenic A beta 42 peptide secretion, but the mechanism is undefined and not COX-dependent.
Purpose of the Study:
- To elucidate the molecular mechanism by which NSAIDs reduce A beta 42 production.
- To investigate the role of gamma-secretase activity and presenilin-1 (PS1) mutations in NSAID response.
Main Methods:
- Cell-based assays to measure intracellular A beta 42 levels.
- Cell-free gamma-secretase activity assays.
- Studies involving overexpression of PS1 and APP mutations.
Main Results:
- NSAIDs reduce intracellular A beta 42 pools and selectively decrease A beta 42 production in cell-free gamma-secretase assays.
- Presenilin-1 (PS1) mutations differentially modulate the cellular response to NSAIDs, with PS1-M146L enhancing and PS1-Delta Exon9 diminishing the A beta 42 lowering effect.
- APP mutations also influenced NSAID response, with V717F enhancing but Swedish mutant APP not affecting it.
Conclusions:
- NSAIDs lower A beta 42 production through direct modulation of gamma-secretase activity or its substrate.
- This mechanism is distinct from COX inhibition and suggests a novel therapeutic avenue for Alzheimer's disease.