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Phosphorylation of beta‐amyloid precursor protein (APP) cytoplasmic tail facilitates amyloidogenic processing during apoptosis
Author(s) -
GottardiLittell Numa R,
Sodhi Chhinder P,
Perez Ruth G
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.167.12
Subject(s) - staurosporine , phosphorylation , microbiology and biotechnology , amyloid precursor protein , biology , secretion , apoptosis , protein kinase a , threonine , protein kinase c , cytoplasm , kinase , serine , biochemistry , alzheimer's disease , medicine , disease
Secretion and progressive cerebral accumulation of β‐amyloid peptides (Aβ) derived by endoproteolytic (‘amyloidogenic’) processing of β‐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 Aβ42 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 Aβ‐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 Aβ‐secretory response. These results are consistent with APP cytoplasmic‐tail phosphorylation at T668 during apoptosis as contributory to increased Aβ42 secretion originating from the endocytotic pathway, likely with cell‐line restriction. This work was supported by NIH grant AG15066 awarded to NR Gottardi‐Littell.