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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
NSAID-based γ-secretase modulators do not bind to the amyloid-β polypeptide
Paul J Barrett1, Charles R Sanders, Stephen A Kaufman
1Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232-8725, United States.
Biochemistry
|October 15, 2011
Summary
Gamma-secretase modulators (GSMs) for Alzheimer's disease may not work by directly binding amyloid-beta. Instead, some GSMs aggregate and nonspecifically trigger amyloid-beta aggregation, challenging current therapeutic hypotheses.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) therapeutics target amyloid-beta (Aβ) production via gamma-secretase modulators (GSMs).
- GSMs are hypothesized to work by directly binding to the Aβ domain of the C-terminal fragment of amyloid precursor protein (C99).
- The precise mechanism of action for GSMs remains poorly understood, necessitating further investigation into their molecular interactions.
Purpose of the Study:
- To investigate the interaction between the GSM sulindac sulfide and amyloid-beta (Aβ) species.
- To determine if NSAID-based GSMs directly bind to Aβ or C99, challenging existing hypotheses.
- To explore the aggregation behavior of GSMs and its potential impact on experimental results.
Main Methods:
- Investigated the binding of monomeric sulindac sulfide to monomeric Aβ42.
- Observed the aggregation properties of sulindac sulfide in solution.
- Examined the binding of flurbiprofen to monomeric Aβ42 and C99 reconstituted into lipid vesicles.
Main Results:
- No direct interaction was found between monomeric sulindac sulfide and monomeric Aβ42.
- Sulindac sulfide was observed to form aggregates that could nonspecifically bind to and induce Aβ42 aggregation.
- Flurbiprofen also failed to bind to monomeric Aβ42 or C99, further questioning direct binding mechanisms.
Conclusions:
- The aggregation of sulindac sulfide can confound binding assay results, suggesting current interpretations may be flawed.
- NSAID-based GSMs likely do not function by directly targeting the Aβ domain of C99.
- These findings challenge the direct binding hypothesis for NSAID-based GSMs and suggest alternative mechanisms of action for Alzheimer's disease therapeutics.
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