title: Mitogen-activated protein kinase signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor-mediated amyloid-β uptake in SH-SY5Y cells.
abstract: Intraneuronal accumulation of beta-amyloid protein (Aβ) is an early pathological change in Alzheimer's disease (AD). Recent studies demonstrate that α7 nicotinic acetylcholine receptor (α7nAChR) binds to soluble Aβ with a high affinity. In vitro and in vivo experiments also show that Aβ activates p38 MAPK and ERK1/2 signaling pathways via the α7nAChR. Interestingly, it has been reported that p38 MAPK and ERK1/2 signaling pathways affect the regulation of receptor-mediated endocytosis. These data suggest that MAPK signaling pathways maybe involved in the regulation of α7nAChR-mediated Aβ uptake. However, the evidence for this hypothesis is lacking. In the present study, we examined whether Aβ1-42 oligomers activate MAPK signaling pathways via α7nAChR, and assessed the role of MAPK signaling pathways in the regulation of Aβ1-42 uptake by α7nAChR. We confirm that undifferentiated SH-SY5Y cells are capable of taking up extracellular Aβ1-42. The internalization of Aβ1-42 accumulates in the endosomes/lysosomes and mitochondria. MAPK signaling pathways are activated by Aβ1-42 via α7nAChR. Aβ1-42 and α7nAChR are co-localized in SH-SY5Y cells and the expression of α7nAChR involves in Aβ1-42 uptake and accumulation in SH-SY5Y cells. Our data demonstrate that Aβ1-42 induces an α7nAChR-dependent pathway that relates to the activation of p38 MAPK and ERK1/2, resulting in internalization of Aβ1-42. Our findings suggest that α7nAChR and MAPK signaling pathways play an important role in the uptake and accumulation of Aβ1-42 in SH-SY5Y cells. Blockade of α7nAChR may have a beneficial effect by limiting intracellular accumulation of amyloid in AD brain and serves a potential therapeutic target for AD.
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: W N
authors.initials: WN
authors.lastname: Yang
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: K G
authors.initials: KG
authors.lastname: Ma
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: X L
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Department of Human Anatomy, Xi'an Medical University, 1 Xinwang Road, Xi'an 710021, China.
authors.forename: L L
authors.initials: LL
authors.lastname: Shi
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: X D
authors.initials: XD
authors.lastname: Hu
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China. Electronic address: qianyh38@mail.xjtu.edu.cn.
authors.forename: Y H
authors.initials: YH
authors.lastname: Qian
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; beta-amyloid protein; mitogen-activated protein kinase signaling pathways; uptake; α7 nicotinic acetylcholine receptor