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Proteolytic processing of amyloid-beta precursor protein by secretases does not require cell surface transport
Mikhail Khvotchev1, Thomas C Südhof
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
The Journal of Biological Chemistry
|August 19, 2004
Summary
Amyloid precursor protein (APP) cleavage and subsequent signaling are impaired by blocking trans-Golgi traffic, suggesting intracellular control rather than cell surface regulation.
Area of Science:
- Cell Biology
- Neuroscience
- Molecular Biology
Background:
- Amyloid precursor protein (APP) cleavage generates fragments, including the APP intracellular domain (AICD), which may regulate transcription.
- The cellular localization and regulation of APP cleavage remain largely unknown, unlike Notch signaling, which is ligand-dependent at the cell surface.
Purpose of the Study:
- To investigate the cellular localization and regulatory mechanisms of APP cleavage.
- To determine the role of intracellular trafficking and protein interactions in APP processing and AICD signaling.
Main Methods:
- Utilized transfected cultured cells expressing full-length and truncated syntaxin 1A proteins.
- Manipulated trans-Golgi traffic and exocytosis using syntaxin 1A fragments.
- Assessed the impact on APP cleavage, APPS and Abeta peptide secretion, and AICD-dependent nuclear signaling.
Main Results:
- Full-length syntaxin 1A disrupted the Golgi apparatus and blocked trans-Golgi traffic and exocytosis.
- Truncated syntaxin 1A selectively inhibited exocytosis without affecting Golgi traffic.
- Blocking trans-Golgi traffic, but not exocytosis alone, significantly impaired APP cleavage and AICD signaling.
Conclusions:
- APP cleavage and AICD-dependent nuclear signaling are dependent on trans-Golgi traffic.
- APP cleavage regulation appears to be controlled by intracellular signaling pathways, distinct from cell surface ligand-dependent mechanisms observed in Notch signaling.