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Secretory processing of the Alzheimer amyloid beta/A4 protein precursor is increased by protein phosphorylation
S L Gillespie1, T E Golde, S G Younkin
1Division of Neuropathology, Case Western Reserve University School of Medicine, Cleveland OH 44106.
Abstract:
The 39-43 residue polypeptide (amyloid beta protein, beta A4) deposited as amyloid in Alzheimer's disease (AD) is derived from a set of 695-770 residue precursors referred to as the amyloid beta A4 protein precursor (beta APP). In each of the 695, 751, and 770 residue precursors, the 43 residue beta A4 is an internal peptide that begins 99 residues from the COOH-terminus of the beta APP. Each holoform is normally cleaved within the beta A4 to produce a large secreted derivative as well as a small membrane associated fragment. Neither of these derivatives can produce amyloid because neither contains the entire beta A4 peptide. In this study, we employ cells stably transfected with full length beta APP695, beta APP751, or beta APP770 expression constructs to show that phorbol ester activation of protein kinase C substantially increases the production of secreted forms from each isoform. By increasing processing of beta APP in the secretory pathway, PKC phosphorylation may help to prevent amyloid deposition.
Insights
Protein kinase C activation enhances the secretion of amyloid beta precursor protein (beta APP) forms. This processing may prevent amyloid deposition in Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid plaque deposition.
- Amyloid beta protein (beta A4) is derived from amyloid beta A4 protein precursor (beta APP).
- beta APP exists in multiple isoforms (e.g., beta APP695, beta APP751, beta APP770).
Purpose of the Study:
- To investigate the effect of protein kinase C (PKC) on beta APP processing and secretion.
- To determine if PKC activation influences the production of secreted beta APP forms.
- To explore the potential role of PKC in preventing amyloid deposition in AD.
Main Methods:
- Utilized cells stably transfected with full-length beta APP695, beta APP751, and beta APP770 expression constructs.
- Administered phorbol ester to activate protein kinase C (PKC).
- Quantified the production of secreted beta APP forms.
Main Results:
- Phorbol ester activation of PKC substantially increased the production of secreted forms from all beta APP isoforms.
- PKC phosphorylation enhances the processing of beta APP within the secretory pathway.
- Increased secretion of beta APP derivatives was observed.
Conclusions:
- PKC activation promotes the secretion of beta APP, potentially reducing amyloidogenic fragments.
- Enhanced processing of beta APP via PKC phosphorylation may serve as a protective mechanism against amyloid deposition in Alzheimer's disease.
- Targeting PKC pathways could be a therapeutic strategy for AD.