Phosphorylation of beta-amyloid precursor protein (APP) cytoplasmic tail facilitates amyloidogenic processing during apoptosis.
Secretion and progressive cerebral accumulation of beta-amyloid peptides (Abeta) derived by endoproteolytic ("amyloidogenic") processing of beta-amyloid precursor protein (APP) represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. We previously demonstrated that secretion of the neurotoxic species Abeta42 increases during staurosporine-induced apoptosis in undifferentiated PC12 cells, in an endocytosis-dependent manner. In the present study, we tested whether phosphorylation of the APP cytoplasmic-tail is contributory to this apoptosis-related increased Abeta-secretory response. We demonstrate that cytoplasmic-tail phosphorylation specifically at amino-acid residue T668 (APP-695 numbering) increases during staurosporine-induced apoptosis, in parallel with activation of the mitogen-activated, proline-directed serine/threonine protein kinase ERK1. We demonstrate additionally that specific ERK inhibition during staurosporine induction, with serum-free conditions, results in down-regulation of APP phosphorylation at T668, together with attenuation of the increased Abeta-secretory response. These results are consistent with APP cytoplasmic-tail phosphorylation at T668 during apoptosis as contributory to increased Abeta42 secretion originating from the endocytotic pathway, likely with cell-line restriction.
Sodhi
Chhinder P
CP
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Perez
Ruth G
RG
Gottardi-Littell
Numa R
NR
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D048052:Mitogen-Activated Protein Kinase 3; D019311:Staurosporine