γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing
Tobias A Weber1,2, Johan Lundkvist1,3,4, Johanna Wanngren1
1Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Stockholm, Sweden.
Abstract:
The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aβ production.
Insights
Gamma-secretase modulators (GSMs) selectively lower amyloid-beta 42 (Aβ42) production in Alzheimer's disease. GSMs primarily target Aβ production, with minimal impact on other gamma-secretase substrates like EphA4 and EphB2.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves the aggregation of beta-amyloid peptide 42 (Aβ42).
- Gamma-secretase enzyme cleaves amyloid precursor protein (APP) to produce various Aβ peptides.
- Gamma-secretase modulators (GSMs) are investigated as potential AD therapeutics by lowering Aβ42 levels.
Purpose of the Study:
- To investigate the selectivity of GSMs on gamma-secretase substrates.
- To determine how GSMs affect the processing of E-cadherin, EphA4, and EphB2 by gamma-secretase.
- To elucidate the impact of GSMs on Aβ-like peptide production from non-APP substrates.
Main Methods:
- Utilized a reporter gene assay to assess gamma-secretase activity.
- Analyzed the cleavage of three specific gamma-secretase substrates: E-cadherin, EphA4, and EphB2.
- Quantified the production of intracellular domains and Aβ-like peptides.
Main Results:
- GSMs did not affect the gamma-secretase-dependent generation of EphA4 and EphB2 intracellular domains.
- Gamma-secretase processing of EphA4 and EphB2 yielded Aβ-like peptides.
- GSMs modulated Aβ-like peptide production from EphA4, but with significantly lower potency than Aβ modulation.
Conclusions:
- GSMs demonstrate selectivity for gamma-secretase-mediated Aβ production.
- The findings support the targeted therapeutic potential of GSMs in Alzheimer's disease.
- GSMs spare the processing of other critical gamma-secretase substrates involved in cell signaling.
