Abstract
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.
Original language | English (US) |
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Pages (from-to) | 204-212 |
Number of pages | 9 |
Journal | Brain research |
Volume | 1198 |
DOIs | |
State | Published - Mar 10 2008 |
Externally published | Yes |
Keywords
- APP
- Apoptosis
- Aβ
- ERK
- MAPK
- Phosphorylation
ASJC Scopus subject areas
- General Neuroscience
- Molecular Biology
- Clinical Neurology
- Developmental Biology