title: Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes.
abstract: The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer's disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1-42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1-42 oligomers in a dose-dependent manner (p < 0.05) and this trend could be recovered by insulin treatment (p < 0.05). However, the expressions of total Akt and mTOR were invariant (p > 0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1-42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions.
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Sleep Medicine Center, Provincial Hospital Affiliated to Shandong University, 9677#, Jingshi Road, Jinan, 250000, People's Republic of China.
authors.forename: Liling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Qinjian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cong
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jingwu Road, Jinan, 250021, People's Republic of China. sdslyydyf@163.com.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D007328:Insulin; D010446:Peptide Fragments; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: Alzheimer’s disease; Aβ1–42 oligomers; Excitatory amino acid transporter; Human astrocytes; Insulin signaling