Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death

We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death.

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Neuroprotective Role of a Proline-Rich Akt Substrate in Apoptotic Neuronal Cell Death after Stroke: Relationships with Nerve Growth Factor

Journal of Neuroscience ◽

10.1523/jneurosci.5209-03.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 1584-1593 ◽

Cited By ~ 82

Author(s):

A. Saito

Keyword(s):

Cell Death ◽

Nerve Growth Factor ◽

Growth Factor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nerve Growth

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Nerve growth factor and neuronal cell death

Molecular Neurobiology ◽

10.1007/bf02935585 ◽

1990 ◽

Vol 4 (1-2) ◽

pp. 57-91 ◽

Cited By ~ 19

Author(s):

J. Regino Perez-Polo ◽

Perry J. Foreman ◽

George R. Jackson ◽

Din-e Shan ◽

Giulio Taglialatela ◽

...

Keyword(s):

Cell Death ◽

Nerve Growth Factor ◽

Growth Factor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nerve Growth

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Neuronal cell death, nerve growth factor and neurotrophic models: 50 years on

Autonomic Neuroscience ◽

10.1016/s1566-0702(01)00358-7 ◽

2002 ◽

Vol 95 (1-2) ◽

pp. 1-23 ◽

Cited By ~ 33

Author(s):

M.R Bennett ◽

W.G Gibson ◽

G Lemon

Keyword(s):

Cell Death ◽

Nerve Growth Factor ◽

Growth Factor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nerve Growth

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Bax promotes neuronal cell death and is downregulated during the development of the nervous system

Development ◽

10.1242/dev.124.6.1239 ◽

1997 ◽

Vol 124 (6) ◽

pp. 1239-1249 ◽

Cited By ~ 1

Author(s):

K. Vekrellis ◽

M.J. McCarthy ◽

A. Watson ◽

J. Whitfield ◽

L.L. Rubin ◽

...

Keyword(s):

Cell Death ◽

Cerebral Cortex ◽

Nerve Growth Factor ◽

Growth Factor ◽

Expression Vector ◽

Sympathetic Neurons ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nerve Growth ◽

Cultured Sympathetic Neurons

The Bcl-2 and Bcl-x proteins suppress programmed cell death, whereas Bax promotes apoptosis. We investigated the pattern of expression of Bcl-2, Bax and Bcl-x during neuronal differentiation and development. All three proteins were widely expressed in neonatal rats but, in the adult, Bax levels were 20- to 140-fold lower in the cerebral cortex, cerebellum and heart muscle, whereas Bcl-x was not downregulated in any of the tissues examined. In the cerebral cortex and cerebellum, the decrease in Bax levels occurred after the period of developmental cell death. Further, microinjection of a Bax expression vector into cultured sympathetic neurons, which depend on nerve growth factor for survival, induced apoptosis in the presence of survival factor and increased the rate of cell death after nerve growth factor withdrawal. This effect could be blocked by co-injection of an expression vector for Bcl-xL or for the baculovirus p35 protein, an inhibitor of caspases (ICE-like proteases). These results suggest that, during development, the sensitivity of neurons to signals that induce apoptosis may be regulated by modulating Bax levels and that Bax-induced death requires caspase activity.

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