Complex relationships between substrate sequence and sensitivity to alterations in γ-secretase processivity induced
Joo In Jung1, Yong Ran, Pedro E Cruz
1Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, and McKnight Brain Institute, College of Medicine, University of Florida , Gainesville, Florida 32603, United States.
Biochemistry
|March 14, 2014
Summary
Gamma-secretase modulators (GSMs) are potential Alzheimer's therapeutics. This study shows that mutations in amyloid precursor protein (APP) can reduce GSM effectiveness, indicating substrate selectivity for therapeutic intervention.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Gamma-secretase cleaves amyloid precursor protein (APP), producing amyloid-beta (Aβ) peptides.
- Mutations in APP and Presenilin (PSEN) linked to familial Alzheimer's disease alter Aβ profiles, increasing pathogenic Aβ42/Aβ43.
- Gamma-secretase modulators (GSMs) and inverse GSMs (iGSMs) modulate Aβ42 levels, with GSMs being of therapeutic interest.
Purpose of the Study:
- To investigate if mutations in the APP transmembrane domain (TMD) affect GSM and iGSM modulation of gamma-secretase cleavage.
- To determine if APP substrate sequence influences GSM/iGSM activity.
Main Methods:
- Evaluated the effect of APP mutations near the TMD luminal border on gamma-secretase cleavage.
- Tested modulation by acidic (NSAID-derived) and nonacidic (phenylimidazole-derived) GSMs and iGSMs.
Main Results:
- Point mutations in APP significantly reduced sensitivity to GSMs.
- APP mutations had weaker effects on iGSM activity.
- GSM effectiveness is dependent on the APP substrate sequence near the extracellular domain/TMD junction.
Conclusions:
- GSM activity is substrate-selective, influenced by the amino acid sequence of the gamma-secretase substrate.
- These findings support the potential for substrate-specific design of GSMs for Alzheimer's disease therapeutics.
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