title: High Glucose Enhances Neurotoxicity and Inflammatory Cytokine Secretion by Stimulated Human Astrocytes.
abstract: Chronic neuroinflammation caused by activation of microglia and astrocytes in the brain contributes to neuronal loss and disease progression in Alzheimer's disease (AD). Recent research has identified type 2 diabetes mellitus (T2DM) as a risk factor for AD. High blood glucose (hyperglycemia) and the phenomenon of insulin resistance are being considered as the major factors contributing to an increased risk of AD. However, the mechanisms involved in this interaction remain unclear.
  
  
  
  High glucose has been shown to increase release of pro-inflammatory mediators from various immune cells, including microglia. Since astrocytes are the most abundant glial cell type in the brain, we investigated the effects of elevated glucose concentrations (5.5-30.5 mM) on selected functions of cultured human astrocytes in the presence of inflammatory stimuli.
  
  
  
  Experiments were conducted using primary human astrocytes and U-118 MG astrocytoma cells.
  
  
  
  High glucose (30.5 mM) increased mRNA expression of interleukin (IL)-6 and secretion of both IL-6 and IL-8 by astrocytes. This astrocytic inflammatory response to high glucose did not appear to be mediated by augmented p38 or p44/42 mitogen activated protein kinase (MAPK) signaling pathways. In addition, high glucose increased the susceptibility of undifferentiated human SH-SY5Y neuronal cells and retinoic-acid differentiated SH-SY5Y cells to injury by hydrogen peroxide (H2O2) and fibrillar amyloid beta-42 protein (Aβ42), respectively.
  
  
  
  Our data indicate that hyperglycemia in T2DM may be one of the factors contributing to the observed increased risk of AD by exacerbating astrocyte-mediated neuroinflammation and neuronal injury caused by disease-associated agents.
authors.affiliation: Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia. Canada.
authors.forename: Manpreet
authors.initials: M
authors.lastname: Bahniwal
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan Campus, Kelowna, British Columbia. Canada.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
authors.affiliation: Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, BC. Canada.
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013549:Sweetening Agents / Q000494:pharmacology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D010446:Peptide Fragments; D012333:RNA, Messenger; D013549:Sweetening Agents; C075222:amyloid beta-protein (1-42); D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Alzheimer's disease; Aβ42; Glucose; astrocytes; hyperglycemia; neuroinflammation; type 2 diabetes mellitus