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Updated: May 29, 2026
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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
Synaptic autoregulation by metalloproteases and γ-secretase
Sophie Restituito1, Latika Khatri, Ipe Ninan
1Department of Biochemistry, New York University Langone Medical Center, New York, New York 10016, USA. restis01@nyumc.org
Summary
Metalloproteases and gamma-secretase regulate synapses by cleaving synaptic proteins. This activity-dependent proteolysis modifies synaptic transmission and offers a new form of synaptic autoregulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Metalloproteases and gamma-secretase cleave substrates beyond amyloid precursor protein.
- Synaptic proteins like N-cadherin are involved in synapse remodeling and maintenance.
- Gamma-secretase is an intramembrane aspartyl protease implicated in Alzheimer's disease.
Purpose of the Study:
- To investigate the physiological roles of metalloproteases and gamma-secretase in synaptic regulation.
- To determine the localization and interactions of these proteases at the synapse.
- To elucidate the impact of their activity on synaptic transmission.
Main Methods:
- Studies were conducted in rat and mouse models.
- Investigated protease localization and interactions using synaptic scaffolding proteins.
- Examined activity-dependent proteolysis and its effects on synaptic protein levels and transmission.
Main Results:
- Metalloproteases and gamma-secretase are confirmed as physiological regulators of synapses.
- Gamma-secretase is localized at the synapse via interaction with scaffolding protein delta-catenin.
- Activity-dependent proteolysis by these enzymes decreases synaptic protein levels and synaptic transmission, with metalloprotease cleavage being NMDA receptor-dependent.
Conclusions:
- Synaptic metalloproteases and gamma-secretase play crucial roles in regulating synaptic function.
- Activity-dependent substrate cleavage by these proteases provides a novel mechanism for synaptic autoregulation.
- These findings offer new insights into the molecular mechanisms governing synaptic plasticity and transmission.
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