Phosphorylation of β-amyloid precursor protein (APP) cytoplasmic tail facilitates amyloidogenic processing during apoptosis

Chhinder P. Sodhi, Ruth G. Perez, Numa R. Gottardi-Littell

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)204-212
Number of pages9
JournalBrain research
Volume1198
DOIs
StatePublished - Mar 10 2008
Externally publishedYes

Keywords

  • APP
  • Apoptosis
  • ERK
  • MAPK
  • Phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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