Activation of the Amyloidogenic Route by NGF Deprivation Induces Apoptotic Death in PC12 Cells

Article type: Research Article

Authors: Matrone, Carmela^a | Di Luzio, Anna^a | Meli, Giovanni^b | D'Aguanno, Simona^{c; d} | Severini, Cinzia^a | Ciotti, Maria Teresa^a | Cattaneo, Antonino^{b; e} | Calissano, Pietro^{a; b; *}

Affiliations: [a] Institute of Neurobiology and Molecular Medicine, CNR, Via del Fosso di Fiorano, 64, 00143 Roma, Italy | [b] EBRI (European Brain Research Institute), Via Fosso del Fiorano 64, Roma, Italy | [c] IRCCS. Fondazione S. Lucia, Via del Fosso di Fiorano, 64, 00143 Roma, Italy | [d] Department of Medicina Interna, University of Rome “Tor Vergata”, Via Montpellier, 1-00133 Roma, Italy | [e] SISSA (International School for Advanced Studies), Via Beirut 2-4, 34013 Trieste, Italy

Correspondence: [*] Corresponding author: Pietro Calissano, Institute of Neurobiology and Molecular Medicine, CNR, Via del Fosso di Fiorano, 64, 00143 Rome, Italy. E-mail: calissano@inmm.cnr.it.

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.

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, apoptosis, neurotrophin, NGF, NGF target neurons

DOI: 10.3233/JAD-2008-13109

Journal: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 81-96, 2008