Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 Cells

Carmela Matrone, Anna Di Luzio, Giovanni Meli, Simona D'Aguanno, Cinzia Severini, Maria Teresa Ciotti, Antonino Cattaneo, Pietro Calissano

Research output: Contribution to journalArticlepeer-review

Abstract

Nerve growth factor (NGF) exerts a trophic, antiapoptotic action on several neuronal targets, including the clonal cell line PC12. In the current study, we demonstrate that withdrawal of this neurotrophin from PC12 differentiated cells causes overproduction of amyloid-β (Aβ) peptides, which are the most toxic protein fragments directly implicated in the development of Alzheimer disease (AD), concomitantly with cell death by apoptosis. Aβ production and apoptotic death, occurring after withdrawal from NGF-differentiated PC12 cells, are completely inhibited by β- and γ-secretase inhibitors and by antibodies directed against Aβ peptides, favouring maintenance of PC12 morphology and neuritic network. These peptides are partially released and largely deposited as aggregates only soluble with strong detergent treatment generally employed to dissolve senile plaques. Furthermore, partial silencing of APP mRNA, by siRNA, reduces not only the extent of Aβ production but also apoptotic death. Aβ production and apoptosis are also induced in differentiated PC12 cells by kinase inhibitors of Trk-A, the high affinity receptor of NGF and, in this case, the co-incubation with β- and γ-secretase inhibitors totally revert apoptosis.

Original languageEnglish
Pages (from-to)81-96
Number of pages16
JournalJournal of Alzheimer's Disease
Volume13
Issue number1
Publication statusPublished - 2008

Keywords

  • Alzheimer disease
  • Amyloid-β
  • Amyloid-β protein precursor
  • Apoptosis
  • Neurotrophin
  • NGF
  • NGF target neurons

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology

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