C6 Glioma-Secreted NGF and FGF2 Regulate Neuronal APP Processing Through Up-Regulation of ADAM10 and Down-Regulation of BACE1, Respectively
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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.
KeywordsAstrocyte C6 glioma cell-conditioned medium ADAM10 BACE1 NGF FGF2
A disintegrin and metalloproteinase domain 10
Amyloid precursor protein
Beta-site amyloid precursor protein-cleaving enzyme 1
Brain-derived neurotrophic factor
Dulbecco’s modified Eagle’s medium
Epidermal growth factor
Fibroblast growth factor 2
Fibroblast growth factor receptor 1
Glioma cell-conditioned medium
Glial cell line-derived neurotrophic factor
Nerve growth factor
High affinity NGF tyrosine kinase receptor
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.
This work was supported by the National Natural Science Foundation of China (31371331).
- Hailer NP, Wirjatijasa F, Roser N, Hischebeth GT, Korf HW, Dehghani F (2001) Astrocytic factors protect neuronal integrity and reduce microglial activation in an in vitro model of N-methyl-D-aspartate-induced excitotoxic injury in organotypic hippocampal slice cultures. Eur J Neurosci 14:315–326CrossRefPubMedGoogle Scholar
- Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2:22CrossRefPubMedPubMedCentralGoogle Scholar
- Katsouri L, Ashraf A, Birch AM, Lee KK, Mirzaei N, Sastre M (2014) Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice. Neurobiol AgingGoogle Scholar
- Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 96:3922–3927CrossRefPubMedPubMedCentralGoogle Scholar
- Martinez R, Gomes FC (2002) Neuritogenesis induced by thyroid hormone-treated astrocytes is mediated by epidermal growth factor/mitogen-activated protein kinase-phosphatidylinositol 3-kinase pathways and involves modulation of extracellular matrix proteins. J Biol Chem 277:49311–49318CrossRefPubMedGoogle Scholar
- Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Investig 113:1456CrossRefPubMedPubMedCentralGoogle Scholar
- Wahlberg LU, Lind G, Almqvist PM, Kusk P, Tornoe J, Juliusson B, Soderman M, Sellden E, Seiger A, Eriksdotter-Jonhagen M, Linderoth B (2012) Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery. J Neurosurg 117:340–347CrossRefPubMedGoogle Scholar
- Yang C, Liu Y, Ni X, Li N, Zhang B, Fang X (2014) Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mice model. NeuropeptidesGoogle Scholar