title: Hyperglycemia Increases the Production of Amyloid Beta-Peptide Leading to Decreased Endothelial Tight Junction.
abstract: OBJECTIVE
  Amyloid beta-peptide (Aβ), the main component of senile plaques in the Alzheimer's disease (AD) brains, is generated from sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretase. Hyperglycemia in diabetes may compromise barrier integrity in endothelial cells (ECs). However, the roles of endothelial APP in response to high glucose (HG) remain to be delineated. The aims of this study were to test whether HG may increase Aβ secretion, thereby leading to heightened paracellular permeability in ECs.
  
  
  METHODS
  We determined the effects of HG on production of Aβ, expression of full-length APP, intercellular permeability, and expression levels of specific junctional proteins in human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  HG at 30 mM significantly stimulated expression of full-length APP accompanied by heightened secretion of Aβ1-42, increased paracellular permeability, and attenuated expression of zona occluden-1 (ZO-1), claudin-5, occludin, and junctional adhesion molecule (JAM)-C in HUVECs; all of which were abolished by the γ-secretase inhibitor BMS299897. Exogenous application of Aβ1-42, but not the reverse peptide Aβ42-1, was sufficient to downregulate the expression of the same junction proteins.
  
  
  CONCLUSIONS
  Hyperglycemia enhances APP expression with increased Aβ production, which downregulates junctional proteins causing increased intercellular permeability in ECs.
authors: Department of Neurology, College of Medicine, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan, Republic of China.
authors: A-Ching
authors: AC
authors: Chao
authors: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
authors: Tai-Chi
authors: TC
authors: Lee
authors: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
authors: Suh-Hang Hank
authors: SH
authors: Juo
authors: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors: Ding-I
authors: DI
authors: Yang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D062507:Claudin-5 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D062793:Occludin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C107466:CLDN5 protein, human; D015815:Cell Adhesion Molecules; D062507:Claudin-5; C448000:JAM3 protein, human; C568985:OCLN protein, human; D062793:Occludin; D010446:Peptide Fragments; D012333:RNA, Messenger; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid precursor protein; High glucose; Human umbilical vein endothelial cells; Junctional permeability