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 language | English |
|---|---|
| Pages (from-to) | 81-96 |
| Number of pages | 16 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 13 |
| Issue number | 1 |
| Publication status | Published - 2008 |
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Keywords
- Alzheimer disease
- Amyloid-β
- Amyloid-β protein precursor
- Apoptosis
- Neurotrophin
- NGF
- NGF target neurons
ASJC Scopus subject areas
- Neuropsychology and Physiological Psychology
Cite this
Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 Cells. / Matrone, Carmela; Di Luzio, Anna; Meli, Giovanni; D'Aguanno, Simona; Severini, Cinzia; Ciotti, Maria Teresa; Cattaneo, Antonino; Calissano, Pietro.
In: Journal of Alzheimer's Disease, Vol. 13, No. 1, 2008, p. 81-96.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 Cells
AU - Matrone, Carmela
AU - Di Luzio, Anna
AU - Meli, Giovanni
AU - D'Aguanno, Simona
AU - Severini, Cinzia
AU - Ciotti, Maria Teresa
AU - Cattaneo, Antonino
AU - Calissano, Pietro
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Amyloid-β
KW - Amyloid-β protein precursor
KW - Apoptosis
KW - Neurotrophin
KW - NGF
KW - NGF target neurons
UR - http://www.scopus.com/inward/record.url?scp=40549100696&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40549100696&partnerID=8YFLogxK
M3 - Article
C2 - 18334760
AN - SCOPUS:40549100696
VL - 13
SP - 81
EP - 96
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -