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 (Abeta) peptides, which are the most toxic protein fragments directly implicated in the development of Alzheimer disease (AD), concomitantly with cell death by apoptosis. Abeta 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 Abeta 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 Abeta production but also apoptotic death. Abeta 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.
Matrone
Carmela
C
Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Via del Fosso di Fiorano 64, Rome, Italy.
Di Luzio
Anna
A
Meli
Giovanni
G
D'Aguanno
Simona
S
Severini
Cinzia
C
Ciotti
Maria Teresa
MT
Cattaneo
Antonino
A
Calissano
Pietro
P
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004358:Drug Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D009414:Nerve Growth Factors / Q000235:genetics*; D016716:PC12 Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases