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hFE65L influences amyloid precursor protein maturation and secretion
S Y Guénette1, J Chen, A Ferland
1Department of Neurology, Massachusetts General Hospital East and Harvard Medical School, Charlestown 02129, USA.
Journal of Neurochemistry
|August 26, 1999
Summary
The FE65-like 1 (hFE65L) protein influences amyloid precursor protein (APP) processing by altering its trafficking. This interaction increases the production of neuroprotective secreted APP (APPs alpha), a key factor in Alzheimer's disease research.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Amyloid precursor protein (APP) processing occurs in secretory and endocytic pathways.
- APP generates both neuroprotective secreted APP (APPs alpha) and Alzheimer's-associated beta-amyloid peptides.
- FE65 family proteins bind the cytoplasmic domain of APP, including sorting signals YTS and YENPTY.
Purpose of the Study:
- To investigate the interaction between hFE65L and APP.
- To determine how hFE65L/APP interaction affects APP trafficking and processing.
- To elucidate the role of the YENPTY sequence in this interaction.
Main Methods:
- Utilized pulse/chase experiments in an inducible H4 neuroglioma cell line.
- Examined APP maturation and secretion upon hFE65L expression induction.
- Analyzed APP binding to hFE65L, focusing on the YENPTY sequence.
Main Results:
- hFE65L binding to APP requires an intact YENPTY clathrin-coated pit internalization sequence.
- Induced hFE65L expression increased the ratio of mature to total cellular APP.
- A three-fold increase in secreted APPs alpha was observed in cells overexpressing hFE65L.
Conclusions:
- hFE65L influences APP processing through altered trafficking within the secretory pathway.
- The YENPTY sequence is critical for APP binding to hFE65L.
- hFE65L overexpression enhances the secretion of neuroprotective APPs alpha, independent of PKC activation or increased APP levels.