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Journal of Molecular Neuroscience

, Volume 59, Issue 3, pp 334–342 | Cite as

C6 Glioma-Secreted NGF and FGF2 Regulate Neuronal APP Processing Through Up-Regulation of ADAM10 and Down-Regulation of BACE1, Respectively

  • Huiping Xie
  • Zhimin Xiao
  • Jian HuangEmail author
Article

Abstract

Excessive accumulation of amyloid-β (Aβ) caused by cleavage of amyloid precursor protein (APP) is thought to be the primary cause of Alzheimer’s disease (AD). Two key enzymes ADAM10 and BACE1 are involved in the initial cleavage of APP, resulting in the onset of two pathways, the amyloidogenic pathway and the non-amyloidogenic pathway, respectively. Altering APP metabolism towards the non-amyloidogenic pathway is thought to reduce Aβ production. It has been reported that, in vivo, exogenous neurotrophic factors make APP apt to entering the non-amyloidogenic pathway. Since astrocytes secrete a battery of neurotrophic factors, we investigated the role of astrocyte-derived factors in the dynamics of Aβ generation in neural cells. Results show that C6 glioma cell-conditioned medium (GCM), obtained from cultured astrocyte-derived C6 glioma cells, inhibit Aβ1-42 production and shift APP processing towards the non-amyloidogenic pathway in APPswe-HEK293 cells. Such effect is attributed to two key APP cleavage enzymes, ADAM10 and BACE1. Two neurotrophic factors in the GCM, nerve growth factor and fibroblast growth factor 2, are responsible for the up-regulation of ADAM10 and down-regulation of BACE1, respectively. Our findings enhance our understanding of the relationship between astrocytes and Aβ generation, indicating that stimulation of astrocytic neurotrophic factors could slow AD progression.

Keywords

Astrocyte C6 glioma cell-conditioned medium ADAM10 BACE1 NGF FGF2 

Abbreviations

Amyloid β-protein

AD

Alzheimer’s disease

ADAM10

A disintegrin and metalloproteinase domain 10

APP

Amyloid precursor protein

BACE1

Beta-site amyloid precursor protein-cleaving enzyme 1

BDNF

Brain-derived neurotrophic factor

DMEM

Dulbecco’s modified Eagle’s medium

EGF

Epidermal growth factor

FGF2

Fibroblast growth factor 2

FGFR1

Fibroblast growth factor receptor 1

GCM

Glioma cell-conditioned medium

GDNF

Glial cell line-derived neurotrophic factor

NGF

Nerve growth factor

TrkA

High affinity NGF tyrosine kinase receptor

Notes

Acknowledgments

We are grateful to Professor Hui Fu (Wuhan University, School of Medicine, China) for critical reading of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (31371331).

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.College of Life SciencesWuhan UniversityWuhanPeople’s Republic of China
  2. 2.SanofiCambridgeUSA

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