title: C6 Glioma-Secreted NGF and FGF2 Regulate Neuronal APP Processing Through Up-Regulation of ADAM10 and Down-Regulation of BACE1, Respectively.
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.
authors.affiliation: College of Life Sciences, Wuhan University, Room 5105, Wuhan, Hubei, 430072, People's Republic of China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Wuhan University, Room 5105, Wuhan, Hubei, 430072, People's Republic of China.|Sanofi, Cambridge, MA, 02142, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: College of Life Sciences, Wuhan University, Room 5105, Wuhan, Hubei, 430072, People's Republic of China. jianhuang@whu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; Astrocyte; BACE1; C6 glioma cell-conditioned medium; FGF2; NGF