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

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-beta ( A beta) peptides, which are the most toxic protein fragments directly implicated in the development of Alzheimer disease ( AD), concomitantly with cell death by apoptosis. A beta production and apoptotic death, occurring after withdrawal from NGF-differentiated PC12 cells, are completely inhibited by beta- and gamma-secretase inhibitors and by antibodies directed against A beta 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 A beta production but also apoptotic death. A beta 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 beta- and gamma-secretase inhibitors totally revert apoptosis.