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

Marina Sycheva,Jeganathan Ramesh Babu,Yuxian Zhang,Jake Sustarich,Vaithinathan Selvaraju,Thangiah Geetha,Marla Gearing

doi:10.3390/brainsci9080204

Marina Sycheva, Jeganathan Ramesh Babu + Show 5 more

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https://doi.org/10.3390/brainsci9080204

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Journal: Brain sciences	Publication Date: Aug 19, 2019
Citations: 14	License type: CC BY 4.0

Affiliation: Auburn University, Emory University

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the primary cause of dementia in elderly individuals
The effect of Pro-nerve growth factor (proNGF) signaling is dependent upon the expression levels of p75 neurotrophin receptor (p75NTR) [25,26]
Postmortem AD human hippocampal samples showed an increase in expression of proNGF and p75NTR receptor compared to control samples [8]

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the primary cause of dementia in elderly individuals. P75NTR expression level is found to be increased after neural injury and its signaling leads to neuronal death and dysfunction [7]. Nerve growth factor (NGF) mediates neuronal survival, differentiation, and maintenance of neurons [10], by binding to TrkA and p75NTR receptors [11,12,13]. Pro-nerve growth factor (proNGF) is cleaved into NGF by matrix metalloproteinase (MMP) [14]. We showed that the expression of MMP-7 was reduced in AD hippocampus, which led to decreased levels of NGF and increased expression of proNGF [8]. ProNGF can promote neuronal apoptosis by binding to p75NTR in neurodegenerative disease [15,16,17]

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