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CNS Neurosci Ther. 2016 Apr;22(4):291-7. doi: 10.1111/cns.12503. Epub 2016 Feb 4.

Hyperglycemia Increases the Production of Amyloid Beta-Peptide Leading to Decreased Endothelial Tight Junction.

Author information

1
Department of Neurology, College of Medicine, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan, Republic of China.
2
Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
3
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Republic of China.

Abstract

AIMS:

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.

CONCLUSION:

Hyperglycemia enhances APP expression with increased Aβ production, which downregulates junctional proteins causing increased intercellular permeability in ECs.

KEYWORDS:

Alzheimer's disease; Amyloid precursor protein; High glucose; Human umbilical vein endothelial cells; Junctional permeability

PMID:
26842741
PMCID:
PMC6492831
DOI:
10.1111/cns.12503
[Indexed for MEDLINE]
Free PMC Article

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