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Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein
G L Caporaso1, S E Gandy, J D Buxbaum
1Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021.
Abstract:
Extracellular deposition of the beta/A4 amyloid peptide is a characteristic feature of the brain in patients with Alzheimer disease. beta/A4 amyloid is derived from the amyloid precursor protein (APP), an integral membrane protein that exists as three major isoforms (APP695, APP751, and APP770). Secreted forms of APP found in blood plasma and cerebrospinal fluid arise by proteolytic cleavage of APP within the beta/A4 amyloid domain, precluding the possibility of amyloidogenesis for that population of molecules. In the present study, we have demonstrated that treatment of PC12 cells with phorbol ester produces a severalfold increase in secretion of APP695, APP751, and APP770. This increase is augmented by simultaneous treatment with the protein phosphatase inhibitor okadaic acid. These data indicate that protein phosphorylation regulates intra-beta/A4 amyloid cleavage and APP secretion. These and other results suggest that APP molecules can normally follow either of two processing pathways: regulated secretion or proteolytic degradation unassociated with secretion.
Insights
Alzheimer disease research reveals amyloid precursor protein (APP) secretion is regulated by protein phosphorylation. This finding suggests APP can be processed via regulated secretion or degradation, impacting amyloidogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer disease is characterized by extracellular beta/A4 amyloid peptide deposition in the brain.
- Beta/A4 amyloid originates from the amyloid precursor protein (APP), which has multiple isoforms (APP695, APP751, APP770).
- Secreted APP forms result from cleavage within the beta/A4 domain, preventing amyloidogenesis.
Purpose of the Study:
- To investigate the role of protein phosphorylation in regulating APP secretion and intra-beta/A4 amyloid cleavage.
- To determine how cellular treatments affect APP processing pathways.
Main Methods:
- Treatment of PC12 cells with phorbol ester.
- Simultaneous treatment with the protein phosphatase inhibitor okadaic acid.
- Quantification of secreted APP isoforms (APP695, APP751, APP770).
Main Results:
- Phorbol ester treatment significantly increased the secretion of all three APP isoforms.
- Okadaic acid further augmented the phorbol ester-induced increase in APP secretion.
- Data suggest protein phosphorylation controls APP cleavage within the beta/A4 domain and subsequent secretion.
Conclusions:
- Protein phosphorylation is a key regulator of APP processing.
- APP molecules can follow distinct pathways: regulated secretion or non-secretory degradation.
- Understanding these pathways may offer insights into Alzheimer disease pathogenesis.