Intramembrane proteolysis by gamma-secretase.
Harald Steiner1, Regina Fluhrer, Christian Haass
1Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany. harald.steiner@med.uni-muenchen.de
The Journal of Biological Chemistry
|July 25, 2008
Summary
Gamma-secretase, crucial for Alzheimer's disease pathology, cleaves amyloid beta-peptide (Abeta). Targeting this enzyme offers therapeutic potential for Abeta-lowering strategies.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Gamma-secretase mediates the final cleavage releasing amyloid beta-peptide (Abeta), a key component of Alzheimer disease (AD) senile plaques.
- The gamma-secretase complex comprises four subunits: presenilin (PS), APH-1, nicastrin, and PEN-2, with PS harboring the active site.
- Mutations in PS are linked to familial AD, increasing neurotoxic Abeta production.
Purpose of the Study:
- To investigate the structure and function of the gamma-secretase complex.
- To explore therapeutic strategies targeting gamma-secretase for Alzheimer disease.
- To differentiate between gamma-secretase inhibitors and modulators concerning Notch signaling.
Main Methods:
- Structural analysis using electron microscopy and chemical cross-linking.
- Biochemical assays to study gamma-secretase activity and complex assembly.
- Evaluation of gamma-secretase inhibitors and modulators in relation to Abeta production and Notch signaling.
Main Results:
- Structural studies revealed a water-containing cavity enabling intramembrane proteolysis.
- Multiple gamma-secretase complexes exist, differing in PS and APH-1 variants, all capable of pathological Abeta production.
- Gamma-secretase inhibitors cause side effects due to Notch signaling interference, while modulators selectively reduce pathological Abeta without affecting Notch signaling.
Conclusions:
- Gamma-secretase is a critical therapeutic target for Alzheimer disease.
- Modulators represent a promising approach by selectively reducing toxic Abeta production while preserving essential physiological functions like Notch signaling.
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